Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer.

The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC.

Discrepancies Between Morphological and Immunohistochemical Classifications Are Associated With Prognoses and Subtypes of Lung Cancer.

Background/aim: Immunohistochemical (IHC) staining has been routinely used to distinguish adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of the lungs; however, it is challenging to obtain an accurate diagnosis, especially for cases with discrepancies between IHC and hematoxylin and eosin (H&E) staining results. This study aimed to clarify the clinicopathological characteristics of these discrepant cases.

Patients And Methods: Tissue microarray specimens from 321 patients with ADC and SCC were used for H&E and IHC staining of thyroid transcription factor 1 (TTF-1), Napsin A, cytokeratin 5/6 (CK5/6), p40, and p63.

Silencing of tumoral carbohydrate sulfotransferase 15 reactivates lymph node pancreatic cancer T cells in mice.

Limited intratumoral T-cell infiltration in pancreatic ductal adenocarcinoma (PDAC) is an obstacle to immunotherapy, yet the efficient approach to enhance tumor-infiltrating T cells is not fully established. Here, we show that tumor-specific knockdown of carbohydrate sulfotransferase 15 (CHST15), a tumor stromal proteoglycan-synthetic enzyme, suppresses tumor growth in a T-cell-dependent manner in a murine model of PDAC. Silencing of tumoral CHST15 unexpectedly expanded CD4 and CD8 T cells in tumor draining LN (TDLN), leading to accelerated accumulation of EdU proliferating CD4 and CD8 T cells and granzyme B CD8 T cells in the tumor.

Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis.

Background: Telomere dysfunction has been reported to be directly involved in carcinogenesis owing to chromosomal instability and immortalization; however, the clinicopathological significance of telomeres remains controversial. We have shown that telomere shortening occurs in normal-appearing duct cells at initiation and then continues during the progression of pancreatic cancer. In this study, we determined the clinicopathological and prognostic value of telomere length (TL) in cancer progression.

GAREM1 is involved in controlling body mass in mice and humans.

The adaptor protein GAREM has two subtypes. Each is involved in Erk activation signaling downstream of the cell growth factor receptor in cultured cells. Regarding their role in individual animals, we have previously reported that mice deficient in GAREM2, which is highly expressed in the brain, exhibit emotional changes.

Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs.

Recent evidence indicates that RNA-dependent RNA polymerase (RdRP) activity of human telomerase reverse transcriptase (hTERT) regulates expression of target genes and is directly involved in tumor formation in a telomere-independent manner. Non-canonical function of hTERT has been considered as a therapeutic target for cancer therapy. We have previously shown that hTERT phosphorylation at threonine 249 (p-hTERT), which promotes RdRP activity, is an indicator of an aggressive phenotype and poor prognosis in liver and pancreatic cancers, using two cohorts with small sample sizes with polyclonal p-hTERT antibody.

Reproducibility and prognostic significance of area of residual tumor (ART) in post-neoadjuvant resections of pancreatic ductal adenocarcinoma.

Background: The pathologic assessments of tumor response after neoadjuvant chemoradiotherapy (NACRT) are critical to improving the prognostic stratification for patients with pancreatic ductal adenocarcinoma (PDAC). Here we clarified the utility of our new grading system based on the area of residual tumor (ART) as compared to existing systems, such as the College of American Pathologists (CAP) and MD Anderson (MDA) score.

Methods: Eight reviewers individually evaluated the tumor regression grade of 30 patients with PDAC based on three types of grading systems.

A Case of Adult Pancreatoblastoma With Novel Mutation and Genetic Heterogeneity.

Background: Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas that mainly occurs in children and involves abnormalities in the WNT/β-catenin pathway, such as mutation. However, the molecular abnormalities in adult pancreatoblastoma are not well known.

Case Presentation: An elderly man, who underwent elective distal pancreatectomy and splenectomy, was referred to our hospital with a mass in the tail of the pancreas.

Relationship between Lung Carcinogenesis and Chronic Inflammation in Rodents.

Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer using rodent models.

Adequate tissue sampling for the assessment of pathological tumor regression in pancreatic cancer.

Standardized pathological evaluation of the regression assessment of neoadjuvant pancreatic cancer is necessary to improve prognostication and compare treatment outcomes in clinical trials. However, appropriate tissue sampling from surgically resected pancreatic cancer after neoadjuvant therapy has not been elucidated. We compared the tumor regression scores in the largest cancer slide determined macroscopically or histologically.

Pathological Changes in Pancreatic Carcinogenesis: A Review.

Despite advances in diagnostics and therapeutics, the prognosis of pancreatic cancer remains dismal. Because of a lack of early diagnostic methods, aggressive local progression, and high incidence of distant metastasis, most pancreatic cancers are inoperable; therefore, the characteristics of early pancreatic cancer have not been well understood. Autopsy studies revealed the characteristics of prediagnostic pancreatic malignancies, including precancerous lesions, early stage pancreatic cancer, and pancreatic cancer without clinical symptoms (occult cancers).

Single Intratracheal Quartz Instillation Induced Chronic Inflammation and Tumourigenesis in Rat Lungs.

Crystalline silica (quartz) is known to induce silicosis and cancer in the lungs. In the present study, we investigated the relationship between quartz-induced chronic inflammation and lung carcinogenesis in rat lungs after a single exposure to quartz. F344 rats were treated with a single intratracheal instillation (i.

Preexisting diabetes mellitus had no effect on the no-observed-adverse-effect-level of acetaminophen in rats.

Information on the safety of chemical substances in patients with various preexisting conditions remains limited. Acetaminophen was added to the basal diet at 0, 80, 253, 800, 2530, or 8000 ppm and administered to type 2 diabetes mellitus rats (GK/Jcl) and the control male rats (Wistar) for 13 weeks. Both strains treated with 8000 ppm acetaminophen (561.

Lung proliferative lesion-promoting effects of left pulmonary ligation in A/J female mice.

This present study was conducted in an attempt to examine proliferative lesion-promoting effect in the lung by compensatory lung growth after left pulmonary ligation. To examine a strong proliferative lesion-promoting effect in the lung, the effects of left pulmonary ligation on lung proliferative lesions induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were examined for 12 weeks. The number of proliferative lesions induced by NNK in the right lung after left pulmonary ligation increased significantly after 12 weeks, indicated by an increase in the weight of the right lung.

Development and Clinical Trials of Nucleic Acid Medicines for Pancreatic Cancer Treatment.

Approximately 30% of pancreatic cancer patients harbor targetable mutations. However, there has been no therapy targeting these molecules clinically. Nucleic acid medicines show high specificity and can target RNAs.

Effects of the expectorant drug ambroxol hydrochloride on chemically induced lung inflammatory and neoplastic lesions in rodents.

Ambroxol hydrochloride (AH) is an expectorant drug used to stimulate pulmonary surfactant and serous airway secretion. Surfactant proteins (SPs) are essential for maintaining respiratory structure and function, although SP expression has also been reported in lung inflammatory and proliferative lesions. To determine whether AH exerts modulatory effects on these lung lesions, we examined its effects on pleural thickening induced by intrathoracic administration of dipotassium titanate (TISMO) in A/JJmsSlc (A/J) mice.

Characteristics of surfactant proteins in tumorigenic and inflammatory lung lesions in rodents.

Surfactant proteins (SPs) are essential for the proper structure and respiratory function of the lungs. There are four subtypes of SPs: SP-A, SP-B, SP-C, and SP-D. The expectorant drug ambroxol hydrochloride is clinically used to stimulate pulmonary surfactant and airway serous secretion.

γH2AX is immunohistochemically detectable until 7 days after exposure of N-bis (2-hydroxypropyl) nitrosamine (DHPN) in rat lung carcinogenesis.

It is known that γH2AX, which is formed when there is a double-strand break in DNA, can act as a sensitive marker of genomic instability. In this experiment, the time-course manner of the expression of γH2AX in the lung was examined in the early phase after treatment with a lung carcinogen, N-bis (2-hydroxypropyl) nitrosamine (DHPN). The expression of γH2AX is expected to be one of the useful markers for lung carcinogenesis in early stages.

Validating the use of napsin A as a marker for identifying tumorigenic potential of lung bronchiolo-alveolar hyperplasia in rodents.

There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is "inflammatory hyperplasia" that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is "latent tumorigenic hyperplasia", which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma.

Suppressive effects of the expectorant drug ambroxol hydrochloride on quartz-induced lung inflammation in F344 rats.

Surfactant proteins (SPs) are essential to respiratory structure and function. The expectorant drug ambroxol hydrochloride is clinically prescribed to stimulate pulmonary surfactant and airway serous secretion. Therefore, ambroxol hydrochloride may affect SP production and pulmonary inflammation.

Chronic mesothelial reaction and toxicity of potassium octatitanate fibers in the pleural cavity in mice and F344 rats.

Fiber-shaped particles of potassium octatitanate (tradename TISMO; chemical formula K2 O·6TiO2 ), which are morphologically similar to asbestos particles, were shown to induce severe proliferative reactions in the pleural mesothelium in a previous experiment carried out over 21 weeks. The present study aims to determine whether these fibers induce malignant mesotheliomas in rodents, and to examine chronic toxicity induced. Additionally, we investigated the specific differences observable between the biological responses to the direct infusion of the fibers alone into the pleural cavity and those induced by the co-administration of the fibers with a known carcinogen.

Activation of MEK1/2-ERK1/2 signaling during NNK-induced lung carcinogenesis in female A/J mice.

The extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is activated by several growth factors and mitogens, and upregulation has been noted in many human cancers, including examples in the lung. In this study, to study the association of ERK1/2 activation with mutation of Kras encoding an upstream activator of ERK1/2 in lung premalignant lesions, we immunohistochemically examined expression of phosphorylated forms of ERK1/2 (pERK1/2) and MAP/ERK kinase 1/2 (pMEK1/2) proteins and correlation between ERK activation and mutation of Kras encoding an upstream activator of ERK1/2, in a mouse lung carcinogenesis model. Female 7-week-old A/J mice were administered a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), then maintained without additional treatment until sacrifice at week 52.

Long-Term Chronic Toxicity and Mesothelial Cell Reactions Induced by Potassium Octatitanate Fibers (TISMO) in the Left Thoracic Cavity in A/J Female Mice.

The present study was conducted to examine the chronic effects of potassium octatitanate fibers (trade name TISMO; chemical formula K2O·6TiO2) on the mouse lung and thoracic cavity. This method of infusion was employed to examine the direct effects of the fibers to the pleura. In the present study, 52- and 65-week experiments were employed to examine the long-term chronic effects after infusion of fiber-shaped TISMO into the thoracic cavities of A/J mice.