Down-regulation of METTL5 inhibits proliferation, migration and invasion of triple-negative breast cancer cells through Wnt/6-catenin signaling pathway / 中国药理学通报

Aim To investigate the role and potential mechanism of methyltransferase-like 5 (METTL5) in triple-negative breast cancer (TNBC) . Methods The expression of METTL5 in TNBC tumor tissues and cell lines was detected by immunohistochemistry and Western blot. After shRNA targeting METTL5 (shRNAMETTL5) was transfected into TNBC cells, cell proliferation, migration and invasion were detected by CCK-8, colony formation, wound healing and Transwell assays, respectively. Western blot was used to detect the expression of Wnt/p-catenin signaling-related key proteins. A xenograft tumor model was constructed to verify the effect of METTL5 knockdown on the growth of TNBC cells and Wnt/p-catenin signaling activity in vivo. Results The expression of METTL5 was up-regulated in TNBC tumor tissues and cell lines (P < 0. 01) . Knockdown of METTL5 significantly inhibited the proliferation, migration and invasion of TNBC cells and reduced the expression of Wnt/p-catenin signaling molecules (3-catenin, cyclin Dl, matrix metalloproteinase (MMP) -2 and MMP-7 (all P < 0. 01) . Knockdown of METTL5 reduced tumor growth and Wnt/pcatenin signaling activity in vivo. Conclusions Knockdown of METTL5 can inhibit the proliferation, migration and invasion of TNBC cells, which may be related to the inhibition of Wnt/p-catenin signaling pathway.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Determination and Mechanism Prediction of Potential Active Ingredients in Erdongtang Based on UHPLC-QqQ-MS and Network Pharmacology / 中国实验方剂学杂志

ObjectiveTo establish an ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry（UHPLC-QqQ-MS） for determination of the active ingredients in Erdongtang， and to predict the targets and pathways of anti-insulin resistance action of this formula. MethodThe analysis was performed on an ACQUITY UPLC BEH C18 column（2.1 mm×100 mm， 1.7 μm） with the mobile phase of 0.1% formic acid aqueous solution（A）-acetonitrile（B） for gradient elution（0-3 min， 90%-87%A； 3-6 min， 87%-86%A； 6-9 min， 86%-83%A； 9-11 min， 83%-75%A； 11-18 min， 75%-70%A； 18-19 min， 70%-52%A； 19-22 min， 52%A； 22-25 min， 52%-5%A； 25-27 min， 5%-90%A； 27-30 min， 90%A）. The contents of active ingredients in Erdongtang was detected by electrospray ionization（ESI） and multiple reaction monitoring（MRM） mode under positive and negative ion modes. On this basis， network pharmacology was applied to predict the targets and pathways of Erdongtang exerting anti-insulin resistance effect. ResultThe 20 active ingredients in Erdongtang showed good linear relationships within a certain mass concentration range， and the precision， stability， repeatability and recovery rate were good. The results of determination showed that the ingredients with high content in 15 batches of samples were baicalein（1 259.39-1 635.78 mg·L-1）， baicalin（1 078.37-1 411.52 mg·L-1）， the ingredients with medium content were mangiferin（148.59-217.04 mg·L-1）， timosaponin BⅡ（245.10-604.89 mg·L-1）， quercetin-3-O-glucuronide（89.30-423.26 mg·L-1）， rutin（46.91-1 553.61 mg·L-1）， glycyrrhizic acid（55.97-391.47 mg·L-1）， neomangiferin（37.45-127.03 mg·L-1）， nuciferine（0.89-63.48 mg·L-1）， hyperoside（6.96-136.78 mg·L-1）， liquiritin（30.89-122.78 mg·L-1）， liquiritigenin（26.64-110.67 mg·L-1）， protodioscin（58.57-284.26 mg·L-1）， the ingredients with low content were wogonin（7.16-20.74 mg·L-1）， pseudoprotodioscin（5.49-22.96 mg·L-1）， ginsenoside Rb1（7.31-23.87 mg·L-1）， ginsenoside Rg1（10.78-28.33 mg·L-1）， ginsenoside Re（7.78-24.76 mg·L-1）， ophiopogonin D（2.08-4.29 mg·L-1）， methylophiopogonanone A（0.74-1.67 mg·L-1）. The results of network pharmacology indicated that the mechanism of anti-insulin resistance exerted by Erdongtang might be related to the phosphatidylinositol 3-kinase/protein kinase B（PI3K/Akt） signaling pathway. ConclusionThe established UHPLC-QqQ-MS has the advantages of simple sample processing， strong exclusivity and high sensitivity， and can simultaneously determine the contents of the main ingredients from seven herbs in Erdongtang， which can lay the foundation for the development of Erdongtang compound preparations. The results of the network pharmacology can provide a reference for the mechanism study of Erdongtang in the treatment of type 2 diabetes mellitus.

Meta-analysis of the efficacy and safety of Saccharomyces boulardii versus Bifidobacterium triple live bacteria in the treatment of pediatric diarrhea / 中国药房

OBJECTIVE To compare the efficacy and safety of Saccharomyces boulardii and Bifidobacterium triple live bacteria in the treatment of pediatric diarrhea. METHODS Retrieved from PubMed， Embase， the Cochrane Library， CBM， Wanfang data， CNKI and VIP， randomized controlled trials （RCTs） about S. boulardii （S. boulardii group） versus Bifidobacterium triple liver bacteria （Bifidobacterium group） were collected. After screening the literature， extracting data and evaluating the quality， meta-analysis was performed by using RevMan 5.3 software. RESULTS A total of 9 RCTs were included， involving 898 patients. Results of meta-analysis showed there was no statistical significance in total response rate [OR＝1.69， 95%CI （0.93， 3.09）， P＝0.09]， duration of diarrhea [MD＝－1.39， 95%CI （－3.35， 0.57）， P＝0.16]， the time of abdominal pain disappearance [MD＝0.09， 95%CI（－0.87， 1.05），P＝0.86] or the incidence of adverse reactions [OR＝0.65， 95%CI （0.05， 8.03）， P＝0.74]. The number of stools in S. boulardii group was significantly less than Bifidobacterium group [MD＝－0.91， 95%CI （－1.80， －0.02）， P＝0.04]. The results of subgroup analysis showed that the duration of diarrhea in children with antibiotic-associated diarrhea in S. boulardii group was significantly shorter than Bifidobacterium group （P＜0.05）. CONCLUSIONS The efficacy and safety of S. boulardii are similar to those of Bifidobacterium in the treatment of diarrhea， but S. boulardii is better than Bifidobacterium in terms of stool number， the duration of diarrhea in children with antibiotic-associated diarrhea.

A molecular approach to triple-negative breast cancer: targeting the Notch signaling pathway

ABSTRACT Introduction Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This phenotype renders triple-negative breast cancer cells refractory to conventional therapies, resulting in poor clinical outcomes and an urgent need for novel therapeutic approaches. Recent studies have implicated dysregulation of the Notch receptor signaling pathway in the development and progression of triple-negative breast cancer. Objective This study aimed to conduct a comprehensive literature review to identify potential therapeutic targets of the Notch pathway. Our analysis focused on the upstream and downstream components of this pathway to identify potential therapeutic targets. Results Modulating the Notch signaling pathway may represent a promising therapeutic strategy to treat triple-negative breast cancer. Several potential therapeutic targets within this pathway are in the early stages of development, including upstream (such as Notch ligands) and downstream (including specific molecules involved in triple-negative breast cancer growth). These targets represent potential avenues for therapeutic intervention in triple-negative breast cancer. Comments Additional research specifically addressing issues related to toxicity and improving drug delivery methods is critical for the successful translation of these potential therapeutic targets into effective treatments for patients with triple-negative breast cancer.

Francisco Javier Muñiz. Cirujano de guerra / Francisco Javier Muñiz. War Surgeon

Francisco Javier Muñiz nació en Monte Grande en 1795 y se graduó de médico en la Facultad de Medicina de la Universidad de Buenos Aires en 1822. Además de la medicina y la paleontología, Muñiz se desempeñó como cirujano de guerra en la guerra con el Brasil y en la guerra de la Triple Alianza. En 1871, encontrándose jubilado, se ofrece como voluntario en la lucha contra la epidemia de fiebre amarilla que asoló a la ciudad de Buenos Aires provocando 14.467 muertos. Muñiz falleció el 8 de abril de 1871 en cumplimiento del deber, contagiado de fiebre amarilla. Médico, periodista, paleontólogo, descubridor de la vacuna nativa contra la viruela y realizador de apuntes de lingüística, Francisco Javier Muñiz, representa uno de los grandes ejemplos para la sociedad argentina. (AU)

Francisco Javier Muñiz was born in Monte Grande in 1795 and graduated as a physician from the Faculty of Medicine of the University of Buenos Aires in 1822. In addition to medicine and paleontology, Muñiz served as a military surgeon in the War with Brazil and in the War of the Triple Alliance. In 1871, when he was retired, he volunteered to fight the yellow fever epidemic that devastated the city of Buenos Aires, causing 14,467 deaths. Muñiz died in the line of duty on April 8, 1871, infected with yellow fever. Doctor, journalist, paleontologist, discoverer of the native vaccine against smallpox and linguistic note-taker, Francisco Javier Muñiz is one of the great examples for Argentinian society. (AU)

Programmed cell death protein 1 is a marker for neoadjuvant chemotherapy response in triple-negative breast cancer

SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.

Diagnostic usefulness of triple biopsies (Skin, Muscle and Nerve) in clinically suspected cases of vasculitis in a tertiary care hospital in Gujarat

Introduction: The term vasculitis refers to a heterogeneous group of diseases, all characterized by inflammation and destruction of blood vessel walls leading to ischemic, thrombotic, and hemorrhagic damage to tissues of central and peripheral nervous system. The main indication for triple biopsy (skin, muscle and nerve) is to rule out peripheral vasculitis neuropathy. However, the drawback is that any systemic inflammatory process may show changes in a skin biopsy and hence these changes need to be interpreted with caution. The aim of this study is to establish the diagnostic yield and the usefulness of the triple biopsies in clinically suspected cases of vasculitis. Material and Methods: The present study was conducted in the Department of General Pathology, SBKS MI & RC, Vadodara over a period of one year (1/1/2022 to 31/12/2022). All the clinically suspected cases of vasculitis received at OPD were included in the study. Any case with either muscle, nerve or skin biopsy reported as inadequate were excluded from the study. Results: On evaluation the usefulness of triple biopsies for vasculitis, we found a very low diagnostic yield with only 3.3% of peripheral nerve biopsy and 0.8% of muscle and nerve biopsy showed definite vasculitis. In case of suspected peripheral/systemic vasculitic neuropathy, nerve biopsy was sufficient in the majority of case and has the diagnostic armamentarium for the evaluation of vasculitis. Conclusion: In conclusion, nerve biopsies provide the best yield for the diagnosis of vasculitis, as opposed to muscle and skin biopsies. The role of triple biopsies as a routine protocol for the evaluation of vasculitis is questionable.

CLINICOPATHOLOGICAL STUDY IN TRIPLE NEGATIVE BREAST CANCER

Background and Objectives: - Carcinoma Breast is most common malignancy in females in USA and second among cases deaths in females (after lung cancer). There is considerable geographic , ethnic and racial variability in Breast cancer in evidence with about 5 fold variation throughout the world. Triple negative breast cancer is a heterogonous disease diagnosed by Immune Histo Chemistry (IHC).Triple Negative Breast cancer is characterized by tumor that do not express ER or PR and HER2neu . Proto typical Triple Negative Brest cancer is aggressive in nature and associate with poor prognosis. The Objectives of this study is to analyse the clinical and Pathological features of Triple Negative Breast Cancer and compare the result with similar studies in literature. Fifty Methods:- cases Triple negative Breast Cancer were included in this study. Clinical and pathological features and treatment were noted. Incidence Result:- of Triple Negative Breast Cancer was 35%. The median age of presentation was 45yrs. There were 4% males Triple negative Breast cancer cases out of female patients, most of patients were Pre (or) Perimenopausal(65%). 4% patients had family history of malignantly. Most common stage of presentation was stage III (46%). In Stage IV, Lung and bone metastasis was common. Ten Patients received Neoadjuvant chemo therapy (NACJ) and disease progressed in 4% while on Neoadjuvant chemotherapy, Even though 45 patients had surgery only 34 were eligible to received Adjuvant Radiotherapy. Total of 18% Patients had either progressive disease while on treatment (8%) (or) recurrence 10%. Eighteen percent patients died due to the disease. 33% patients on follow up. There were more Invasive Duct Cell carcinoma (IDCC) cases with medullary differentiations (or) Purse medullary Carcinomas (12%). No deaths Occur in the medullary variants TNBC. Majority of the tumor were high grade margins were negative in most of the cases. Incidence of Tri Inclusion:- ple negative breast cases was higher than western literature but comparable to Indian Studies. The age of Presentation was about 10 years younger than western data. Triple Negative Breast cancer was more common in young, pre (or) perimenopausal women. Small number of patients had family history, majority were state II (or) III. There was high number of progressive disease, recurrence and death while on the study (or) within less than 1 yr of treatment. Triple Negative Breast cancer is very aggressive disease with relatively better prognosis in the medullary variant Triple Negative Breast Cancer.

Carcinoma de mama triple negativo. Estudio anatomo-estadístico / Triple- negative breast cancer. An anatomical and statistical study

Introducción: El carcinoma de mama triple negativo se asocia a un comportamiento biológico más agresivo y de desfavorable pronóstico. Objetivo: Determinar la incidencia del subtipo molecular triple negativo en carcinomas mamarios y su relación con otras variables clínico-patológicas de valor pronóstico. Método: Se realizó un estudio descriptivo y retrospectivo, en el Hospital Universitario Docente «Celestino Hernández Robau» de Villa Clara, en el período comprendido de enero de 2017 a junio de 2019, con el fin de determinar la incidencia de los tumores triples negativos y su relación con las variables edad, talla tumoral, tipo y grado histológicos e índice de proliferación. Resultados: Se determinó la incidencia del subtipo molecular triple negativo en carcinomas mamarios y su relación con las formas histológicas moderada y poco diferenciadas. Conclusiones: El subtipo molecular triple negativo en carcinomas mamarios está asociado con frecuencia a: la edad posmenopáusica, el tipo histológico ductal, el grado histológico alto, altos índices de Ki-67 y talla tumoral mayor de 2 cm.

Introduction: triple-negative breast cancer has a more aggressive biological behaviour and is associated with an unfavourable prognosis. Objective: to determine the incidence of triple- negative breast cancer molecular subtypes and its relationship with other clinical and pathological variables of prognostic value. Methods: a descriptive and retrospective study was carried out at "Celestino Hernández Robau" University Teaching Hospital from Villa Clara between January 2017 and June 2019 in order to determine the incidence of triple- negative tumors and its relationship with the variables: age, tumor size, histological type and grade as well as proliferative index. Results: the incidence of triple- negative breast cancer molecular subtype and its relationship with moderate and poorly differentiated histological forms were determined. Conclusions: triple- negative breast cancer molecular subtype is frequently associated with postmenopausal age, ductal histological type, high histological grade, high Ki-67 indices and tumor size greater than 2 cm.

Atypical Presentation of Anti-phospholipid Syndrome with Triple Antibody Positive (ATAP) Syndrome Presented as Non-healing Foot Ulcer in a Middle-aged Adult Female

Middle aged women presented with non-healing ulcer over foot following trivial injury. She was not having any comorbid condition. Investigations revealed APLA Syndrome with triple antibodies positive (Lupus anticoagulant, Anticardiolipin antibody and anti B2-glycoprotein antibodies). Patient responded well with anti-platelet and skin grafting at local site.

Comunidade rural do Nordeste brasileiro: um cenário de reflexão para a formulação de políticas de desenvolvimento local e empreendedorismo sustentável / Comunidad rural del Noreste brasileño: un escenario de reflexión para la formulación de políticas de desarrollo local y emprendimiento sostenible / The rural community in Northeast Brazil: a scenario of reflection to formulate local development and sustainable entrepreneurship policies

Resumo Este artigo pretende analisar experiências de empreendedorismo sustentável na comunidade rural José Gomes, Nordeste do Brasil, e promover uma reflexão sobre a relevância das políticas de desenvolvimento local na construção de projetos coletivos regionais. Este estudo caracteriza-se como exploratório e descritivo na abordagem qualitativa. Para tanto, foram utilizados técnicas rapport, entrevistas semiestruturadas (82 moradores), observação direta e diário de campo, além de pesquisas bibliográficas. A pesquisa abordou as políticas de desenvolvimento local como mecanismos de avanço e melhoria na qualidade de vida, na organização econômica e na conservação do meio ambiente, que devem ser incorporadas ao planejamento municipal e às ações do poder público. Os resultados apontaram potencialidades socioprodutivas e limitações estruturais e infraestruturais que esgotam as possibilidades de difusão do empreendedorismo sustentável e a consolidação do desenvolvimento local.

Resumen Este artículo pretende analizar experiencias de emprendimiento sostenible en la comunidad rural José Gomes, Nordeste de Brasil, y promover una reflexión sobre la relevancia de las políticas de desarrollo local en la construcción de proyectos colectivos regionales. Se utilizaron técnicas de rapport, entrevistas semiestructuradas (82 residentes), observación directa y diario de campo, además de la investigación bibliográfica. Las políticas de desarrollo local se entendieron como mecanismos para el avance y mejoramiento de la calidad de vida, la organización económica y la conservación del medio ambiente que deben incorporarse a la planificación municipal y a las acciones del poder público. Los resultados apuntaron potencialidades socioproductivas y limitaciones estructurales e infraestructurales que agotan las posibilidades de difundir el emprendimiento sostenible y consolidar el desarrollo local.

Abstract This article analyzes experiences of sustainable entrepreneurship in the José Gomes rural community in Northeast Brazil, reflecting on the relevance of local development policies in the construction of local collective projects. This qualitative, exploratory, and descriptive study adopted rapport techniques, semi-structured interviews (82 dwellers), direct observation, field diary, and bibliographic research. Local development policies were understood as mechanisms for advances and improvements in the quality of life, economic organization, and environmental conservation, which must be incorporated into municipal planning and governmental actions. The results pointed to socio-productive potentials and structural and infrastructural limitations, which hamper the possibilities of spreading sustainable entrepreneurship and consolidating local development.

BRCA1 promoter methylation & its immunohistochemical correlation in sporadic breast cancer

Background & objectives: Studies have shown that apart from hereditary breast carcinomas, breast cancer susceptibility gene 1 (BRCA1) mutations conferring to its loss are seen in sporadic breast carcinomas (SBC) as well. The aim of the present study was to assess BRCA1 methylation in females presenting at King George’s Medical University, Lucknow, with SBC by both immunohistochemistry (IHC) and methylation PCR with respect to hormonal profile and various morphological prognostic parameters. The primary objective was to look for the association between BRCA1 protein expression and DNA promoter methylation. Methods: 81 mastectomy specimens from SBC of invasive breast carcinoma (no special type) were included in this study. After a detailed morphological assessment, formalin fixed paraffin embedded tissue from a representative tumour area was selected for BRCA1 IHC by heat-mediated antigen retrieval under high pH and DNA extraction and further bisulphate treatment. BRCA1 was studied for methylation by methylated and unmethylated PCR-specific primers. Results: BRCA1 promoter methylation was present in 42/81 (51.9%) participants, with significant BRCA1 protein loss (72.7%; P=0.002). A significant association between BRCA1 loss and hormonal profile was found (P=0.001); maximum in triple negative breast carcinoma (TNBC) (72%; 18/25). Most of the TNBC also harboured methylation (68%). Although not significant grade II and III tumours, lymph vascular invasion, ductal carcinoma in situ, and nodal metastasis (?3) were seen in a higher percentage in methylated tumours. Mortality in SBC was significantly associated with BRCA1 loss (30.3%; P=0.024). Interpretation & conclusions: Study results highlight the concept of “BRCAness” in SBC as well. Hence, we can confer that identification of BRCA1 loss in SBC can make it a perfect candidate for poly ADP- ribose polymerase inhibitors or cisplatin-based therapy like hereditary ones.

Research Progress on Immunization and Targeted Therapy for Triple-negative Breast Cancer / 肿瘤防治研究

Triple-negative breast cancer (TNBC) accounts for approximately 15%–20% of all breast cancers. Patients with TNBC have a rapidly progressive clinical course, an earlier age of onset, faster distant recurrence, and more common visceral metastases as compared with other subtypes. However, treatment of TNBC is often limited to chemotherapy and has a poor prognosis. Therefore, developing the best treatment strategy for patients is essential to reduce the burden of disease caused by TNBC. Various potential available drug targets have been discovered, as well as precision treatment and classified treatment are changing the clinical practice of TNBC, thereby indicating a new therapeutic area for TNBC in addition to traditional chemotherapy. This article reviews the systemic treatment options for TNBC in recent years, including immunotherapy and targeted therapy.

Comparison of Clinicopathological Characteristics Between Primary and Contralateral Cancers in BRCA1/2 Carriers with Metachronous Bilateral Breast Cancers / 肿瘤防治研究

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

Research Progress on Genetic Susceptibility to Triple-Negative Breast Cancer / 肿瘤防治研究

Triple-negative breast cancer (TNBC) is a type of breast cancer that is difficult to treat, has a poor prognosis, and is prone to recurrence and metastasis in the early postoperative period. The age of patients is tending younger, and the racial difference is large. It is also related to family history, and genetic susceptibility is obvious. So, elucidating the genetic risk factors of TNBC and obtaining precise therapeutic targets are urgent tasks. Obtaining reliable characteristic genes and their polymorphisms between TNBC of different subtypes is difficult. This review summarizes the susceptibility genes and the polymorphisms of TNBC susceptibility genes of different molecular subtypes, in order to develop effective TNBC prevention strategies and find effective therapeutic targets. This review provides a theoretical basis for promoting the study of TNBC from the perspective of genetics.

Success rate of helicobacter pylori eradication using vonoprazan-based triple therapy as first-line treatment at a tertiary hospital in Baguio City

Background@#Helicobacter pylori is acknowledged to cause chronic gastritis and peptic ulcer disease and is also implicated in gastric carcinoma and B cell mucosa-associated lymphoid tissue (MALT) lymphoma development. It has infected at least half of the world’s population. Proton Pump Inhibitors (PPIs) have been the conventional antacid of choice for H. pylori eradication triple therapy, while vonoprazan is a novel drug of its class that was recently studied but is limited to an oral form which makes it less feasible in cases of acute gastrointestinal bleeding. According to several systematic reviews and meta-analyses, the vonoprazan-based triple therapy regimen for H. pylori eradication is a non-inferior treatment to traditional PPI-based treatment when given in 1 week for patients having no active gastrointestinal bleeding. Likewise, a safety profile has been established with its use, offering an alternative treatment option.@*Objectives@#The research aims to identify the H. pylori eradication rate among H. pylori-positive patients who received a vonoprazan-based triple therapy regimen as outpatients, describe their clinicodemographic profile, and identify potential side effects associated with the treatment.@*Methods@#This study utilized a cross-sectional study design in a single tertiary institution from January 2018 to December 2020. Descriptive and inferential statistics were used in data analysis. Frequency and percentage were utilized to determine the success and failure rates of H. pylori eradication, describe the clinicodemographic profile of patients who underwent vonoprazan-based triple therapy, and the potential side effects with treatment. The chi-square test of independence was applied to assess the significant difference in the successful and failed eradication rates across the clinicodemographic profile. A P-value of <0.05 was considered statistically significant, and statistical analyses were conducted using SPSS version 20.0.@*Results@#32 (91%) had successful H. pylori eradication, with the majority of them determined by a negative 13C-UBT result (62.8%) and the rest with a negative H. pylori stool antigen test (28.6%). The majority of patients undergoing H. pylori eradication using a vonoprazan-based regimen with documented successful eradication belonged to the 19 to 39 years old group (50%), clerical support workers (40.63%), with a chief complaint of abdominal pain (46.88%), with no known co- morbid illness (75%), and with endoscopic finding limited to antral gastritis alone (46.88%). This study described only two documented side effects of treatment: diarrhea and abdominal pain (2.9%).@*Conclusion@#Vonoprazan-based triple therapy, given at 20 mg twice daily for 7 days, has shown a high H. pylori eradication rate among hemodynamically stable patients, without active bleeding, and treated on an outpatient basis. There was a significant difference in eradication success and failure across co-morbidities, with a higher success rate in those without co-morbid illness. A high success rate was also seen in patients <40 years of age, with a single chief complaint, and with antral gastritis as the sole endoscopic finding.

Hydnocarpin inhibits malignant progression of triple negative breast cancer via CNOT4-mediated ubiquitination and degradation of YAP / 中国中药杂志

This study aims to investigate the effect and mechanism of hydnocarpin(HC) in treating triple negative breast cancer(TNBC). Cell counting kit-8(CCK-8), xCELLigence real-time cellular analysis(RTCA), and colony formation assay were employed to determine the effects of HC on the proliferation of two TNBC cell lines: MDA-MB-231 and MDA-MB-436. The effects of HC on the migration and invasion of TNBC cells were detected by high-content analysis, wound-healing assay, and Transwell assay. The changes in the epithelial-mesenchymal transition(EMT) and the expression of invasion-and migration-associated proteins [E-cadherin, vimentin, Snail, matrix metalloproteinase-2(MMP-2), and MMP-9] were detected by Western blot. Western blot and RT-qPCR were employed to determine the protein and mRNA levels of Yes-associated protein(YAP) and downstream targets(CTGF and Cyr61). TNBC cells were transfected with Flag-YAP for the overexpression of YAP, and the role of YAP as a key target for HC to inhibit TNBC malignant progression was examined by CCK-8 assay, Transwell assay, and wound-healing assay. The pathway of HC-induced YAP degradation was detected by the co-treatment of proteasome inhibitor with HC and ubiquitination assay. The binding of HC to YAP and the E3 ubiquitin ligase Ccr4-not transcription complex subunit 4(CNOT4) was detected by microscale thermophoresis(MST) assay and drug affinity responsive target stability(DARTS) assay. The results showed that HC significantly inhibited the proliferation, colony formation, invasion, and EMT of TNBC cells. HC down-regulated the protein and mRNA levels of CTGF and Cyr61. HC down-regulated the total protein level of YAP, while it had no effect on the mRNA level of YAP. The overexpression of YAP antagonized the inhibitory effects of HC on the proliferation, migration, and invasion of TNBC cells. HC promoted the degradation of YAP through the proteasome pathway and up-regulated the ubiquitination level of YAP. The results of MST and DARTS demonstrated direct binding between HC, YAP, and CNOT4. The above results indicated that HC inhibited the malignant progression of TNBC via CNOT4-mediated degradation and ubiquitination of YAP.

Stapled anoplin peptide combined with photothermal therapy enhances oncolytic immunotherapy of triple-negative breast cancer / 中国中药杂志

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.