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BACKGROUND: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers. METHODS: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort. RESULTS: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%). CONCLUSIONS: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer.
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The early mechanisms of spontaneous tumor initiation that precede malignancy are largely unknown. We show that reduced aPKC levels correlate with stem cell loss and the induction of revival and metaplastic programs in serrated- and conventional-initiated premalignant lesions, which is perpetuated in colorectal cancers (CRCs). Acute inactivation of PKCλ/ι in vivo and in mouse organoids is sufficient to stimulate JNK in non-transformed intestinal epithelial cells (IECs), which promotes cell death and the rapid loss of the intestinal stem cells (ISCs), including those that are LGR5+. This is followed by the accumulation of revival stem cells (RSCs) at the bottom of the crypt and fetal-metaplastic cells (FMCs) at the top, creating two spatiotemporally distinct cell populations that depend on JNK-induced AP-1 and YAP. These cell lineage changes are maintained during cancer initiation and progression and determine the aggressive phenotype of human CRC, irrespective of their serrated or conventional origin.
Subject(s)
Colorectal Neoplasms , Epithelial Cells , Metaplasia , Protein Kinase C , Animals , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/genetics , Protein Kinase C/metabolism , Protein Kinase C/genetics , Metaplasia/pathology , Metaplasia/metabolism , Mice , Humans , Epithelial Cells/metabolism , Epithelial Cells/pathology , Stem Cells/metabolism , Stem Cells/pathology , Transcription Factor AP-1/metabolism , Transcription Factor AP-1/genetics , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , YAP-Signaling Proteins/metabolism , Cell Transformation, Neoplastic/pathology , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/deficiency , Organoids/metabolism , Organoids/pathology , Cell Lineage , Isoenzymes/metabolism , Isoenzymes/genetics , Isoenzymes/deficiency , Neoplastic Stem Cells/pathology , Neoplastic Stem Cells/metabolismABSTRACT
BACKGROUND: Chemokine signaling within the tumor microenvironment can promote tumor progression. Although CCR1 and CXCR2 on myeloid cells could be involved in tumor progression, it remains elusive what effect would be observed if both of those are blocked. METHODS: We employed two syngeneic colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. We generated double-knockout mice for CCR1 and CXCR2, and performed bone marrow (BM) transfer experiments in which sub-lethally irradiated wild-type mice were reconstituted with BM from either wild-type, Ccr1-/-, Cxcr2-/- or Ccr1-/-Cxcr2-/- mice. RESULTS: Myeloid cells that express MMP2, MMP9 and VEGF were accumulated around both types of tumors through CCR1- and CXCR2-mediated pathways. Mice reconstituted with Ccr1-/-Cxcr2-/- BM exhibited the strongest suppression of tumor growth and liver metastasis compared with other three groups. Depletion of CCR1+CXCR2+ myeloid cells led to a higher frequency of CD8+ T cells, whereas the numbers of Ly6G+ neutrophils, FOXP3+ Treg cells and CD31+ endothelial cells were significantly decreased. Furthermore, treatment with a neutralizing anti-CCR1 mAb to mice reconstituted with Cxcr2-/- BM significantly suppressed tumor growth and liver metastasis. CONCLUSION: Dual blockade of CCR1 and CXCR2 pathways in myeloid cells could be an effective therapy against colorectal cancer.
Subject(s)
Mice, Knockout , Myeloid Cells , Receptors, CCR1 , Receptors, Interleukin-8B , Tumor Microenvironment , Animals , Receptors, CCR1/metabolism , Receptors, CCR1/genetics , Receptors, CCR1/antagonists & inhibitors , Receptors, Interleukin-8B/antagonists & inhibitors , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/metabolism , Mice , Myeloid Cells/metabolism , Myeloid Cells/immunology , Liver Neoplasms/secondary , Liver Neoplasms/immunology , Liver Neoplasms/pathology , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/metabolism , Mice, Inbred C57BL , Cell Line, Tumor , CD8-Positive T-Lymphocytes/immunologyABSTRACT
Since inorganic nanoparticles have unique properties that differ from those of bulk materials, their material applications have attracted attention in various fields. In order to utilize inorganic nanoparticles for functional materials, they must be dispersed without agglomeration. Therefore, the surfaces of inorganic nanoparticles are typically modified with organic ligands to improve their dispersibility. Nevertheless, the relationship between the tail group structure in organic ligands and the dispersibility of inorganic nanoparticles in organic solvents remains poorly understood. We previously developed amphiphilic ligands that consist of ethylene glycol chains and alkyl chains to disperse inorganic nanoparticles in a variety of organic solvents. However, the structural requirements for amphiphilic ligands to "flexibly" disperse nanoparticles in less polar to polar solvents are still unclear. Here, we designed and synthesized several phosphonic acid ligands for structure-function relationship studies of flexdispersion. Dynamic light scattering analysis and visible light transmittance measurements revealed that the ratio of alkyl/ethylene glycol chains in organic ligands alone does not determine the dispersibility of the nanoparticles in organic solvents, but the arrangement of the individual chains also has an effect. From a practical application standpoint, it is preferable to design ligands with ethylene glycol chains on the outside relative to the particle surface.
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BACKGROUND: Colorectal cancer (CRC) is a global health concern, with advanced-stage diagnoses contributing to poor prognoses. The efficacy of CRC screening has been well-established; nevertheless, a significant proportion of patients remain unscreened, with > 70% of cases diagnosed outside screening. Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources, the association between the diagnostic routes and identification of these subgroups has been less appreciated. In the Japanese cancer registry, the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms. AIM: To clarify the stage at CRC diagnosis based on diagnostic routes. METHODS: We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals. The diagnostic routes were primarily classified into three groups: Cancer screening, follow-up, and symptomatic. The early-stage was defined as Stages 0 or I. Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups, referencing the follow-up group. The adjusted covariates were age, sex, and tumor location. RESULTS: Of the 2083 patients, 715 (34.4%), 1064 (51.1%), and 304 (14.6%) belonged to the follow-up, symptomatic, and cancer screening groups, respectively. Among the 2083 patients, CRCs diagnosed at an early stage were 57.3% (410 of 715), 23.9% (254 of 1064), and 59.5% (181 of 304) in the follow-up, symptomatic, and cancer screening groups, respectively. The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group [P < 0.001, adjusted odds ratio (aOR), 0.23; 95% confidence interval (95%CI): 0.19-0.29]. The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups (P = 0.493, aOR for early-stage diagnosis in the cancer screening group vs follow-up group = 1.11; 95%CI = 0.82-1.49). CONCLUSION: CRCs detected during hospital visits for comorbidities were diagnosed earlier, similar to cancer screening. CRC screening should be recommended, particularly for patients without periodical hospital visits for comorbidities.
Subject(s)
Colonoscopy , Colorectal Neoplasms , Humans , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Early Detection of Cancer , Logistic Models , Retrospective Studies , Male , FemaleABSTRACT
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
Subject(s)
Protein Kinase C , Signal Transduction , Animals , Humans , Mice , Cell Transformation, Neoplastic/genetics , Cholesterol , Epithelial Cells/metabolism , Protein Kinase C/genetics , Protein Kinase C/metabolismABSTRACT
The evolutionary origin of the jaw remains one of the most enigmatic events in vertebrate evolution. The trigeminal nerve is a key component for understanding jaw evolution, as it plays a crucial role as a sensorimotor interface for the effective manipulation of the jaw. This nerve is also found in the lamprey, an extant jawless vertebrate. The trigeminal nerve has three major branches in both the lamprey and jawed vertebrates. Although each of these branches was classically thought to be homologous between these two taxa, this homology is now in doubt. In the present study, we compared expression patterns of Hmx, a candidate genetic marker of the mandibular nerve (rV3, the third branch of the trigeminal nerve in jawed vertebrates), and the distribution of neuronal somata of trigeminal nerve branches in the trigeminal ganglion in lamprey and shark. We first confirmed the conserved expression pattern of Hmx1 in the shark rV3 neuronal somata, which are distributed in the caudal part of the trigeminal ganglion. By contrast, lamprey Hmx genes showed peculiar expression patterns, with expression in the ventrocaudal part of the trigeminal ganglion similar to Hmx1 expression in jawed vertebrates, which labeled the neuronal somata of the second branch. Based on these results, we propose two alternative hypotheses regarding the homology of the trigeminal nerve branches, providing new insights into the evolutionary origin of the vertebrate jaw.
ABSTRACT
Background: Pelvic lymphocele (lymphocyst) infection after lymphadenectomy is a rare complication that can cause the spread of inflammation to neighboring organs whose microbiology is not well known. Cutibacterium avidum causes various infections. However, no case reports of C. avidum pelvic lymphocele infection are available; therefore, its clinical characteristics in pelvic lymphocele infections remain unknown. Case presentation: A 38-year-old woman with obesity (body mass index: 38.1 kg/m2) and a history of pelvic lymphadenectomy and chemotherapy for endometrial cancer presented with worsening left lower quadrant (LLQ) pain with fever. Physical examination revealed decreased abdominal bowel sounds and tenderness on LLQ palpation with no signs of peritonitis. Computed tomography (CT) revealed an infected left pelvic lymphocele with inflammation spreading to the adjacent sigmoid colon. Following blood culture, ampicillin/sulbactam (2 g/1 g every 6 h) was administered intravenously. Anaerobic culture bottles revealed gram-positive rods on day 4 of incubation at 37 °C. No other disseminated foci were observed in enhanced whole-body CT and upon transthoracic echocardiography. The isolates grew aerobically and anaerobically on blood agar plates with strong hemolysis. The bacterium was identified as C. avidum using a combination of characteristic peak analysis with matrix-assisted laser desorption ionization (MALDI) and 16S rRNA gene sequencing. The patient was diagnosed with C. avidum pelvic lymphocele infection. Based on penicillin susceptibility, the patient was successfully treated with intravenous ampicillin/sulbactam and de-escalated with intravenous ampicillin (2 g every 6 h) for 10 days, followed by oral amoxicillin (2000 mg/day) for an additional 11 days without drainage. Conclusions: C. avidum should be considered a causative microorganism of pelvic lymphocele infection. Peak analysis using MALDI and distinctive growth on blood agar plates are suitable for identifying C. avidum. Mild pelvic lymphocele caused by C. avidum can be treated with a short course of appropriate antimicrobial treatment without surgical intervention.
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RATIONALE: Clinically, vertebral osteomyelitis commonly occurs in immunocompromised individuals, such as people with diabetes, immunosuppression, chronic liver disease, and malignancy. Microbiologically, vertebral osteomyelitis is commonly caused by Staphylococcus aureus; however, Streptococcus dysgalactiae subspecies equisimilis (SDSE) may also potentially cause vertebral osteomyelitis, albeit rarely. Since no case reports have documented the occurrence of SDSE cervical osteomyelitis accompanied by progressive atlantoaxial subluxation, its clinical characteristics remain uncertain. Herein, we report the first case of progressive atlantoaxial subluxation in addition to cervical osteomyelitis due to septic atlantoaxial arthritis caused by SDSE in an immunocompetent individual, and provide a review of the relevant literature. PATIENT CONCERNS: A 63-year-old man with hypertension but no history of trauma or musculoskeletal disorders presented with worsening neck pain for 1 month without fever. Physical examination revealed neck pain due to neck retroflexion and tenderness with swelling of the upper cervical spine. No neurological deficit was observed. Magnetic resonance imaging revealed low-intensity areas on a T1-weighted image and high-intensity areas on a short tau inversion recovery image at the C2, C5, and C6 vertebral bodies with atlantoaxial subluxation. Two sets of blood culture tests (aerobic and anaerobic) were performed. DIAGNOSES: The anaerobic blood culture bottle showed the presence of beta-hemolytic pyrrolidonyl arylamidase-negative SDSE expressing Lancefield group A antiserum. Hence, the patient was diagnosed with SDSE cervical osteomyelitis with atlantoaxial subluxation; intensive intravenous ampicillin (2 g every 6 hours) - which is effective against SDSE - was administered. INTERVENTIONS: Posterior fusion (occipital bone, C4) was performed on day 33 because a follow-up magnetic resonance imaging on day 31 revealed progression of atlantoaxial subluxation with thickened atlantodental soft tissue. OUTCOMES: The patient's neck pain was completely relieved after treatment with intravenous ampicillin for 6 weeks, followed by oral amoxicillin (1500 mg) daily for an additional 4 weeks. The patient did not experience recurrence or sequelae during the 2-year follow-up period. LESSONS: SDSE expressing Lancefield group A antiserum can cause afebrile vertebral osteomyelitis and progressive atlantoaxial subluxation due to the occurrence of septic atlantoaxial arthritis in immunocompetent individuals. Spinal instrumentation for vertebral osteomyelitis may be acceptable after 6 weeks of antimicrobial therapy.
Subject(s)
Arthritis, Infectious , Joint Dislocations , Neck Injuries , Osteomyelitis , Male , Humans , Middle Aged , Neck Pain , Osteomyelitis/complications , Osteomyelitis/drug therapy , Cervical Vertebrae , AmpicillinABSTRACT
Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.
Subject(s)
Colorectal Neoplasms , Monocytes , Humans , Male , Animals , Mice , Immunosuppression Therapy , Aggression , Immune Checkpoint Inhibitors , Tumor MicroenvironmentABSTRACT
RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast-like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , Animals , Humans , Mice , Cadherins/genetics , Carcinoma, Pancreatic Ductal/genetics , Epithelial-Mesenchymal Transition/genetics , GPI-Linked Proteins/genetics , Liver Neoplasms/genetics , Pancreas , Pancreatic Neoplasms/genetics , Pancreatic NeoplasmsABSTRACT
TTF-1 is a highly useful marker to assist in differentiating between pulmonary and nonpulmonary, nonthyroid adenocarcinomas. Our case shows that TTF-1 is highly useful in differentiating between pancreatic metastasis from lung adenocarcinoma and primary pancreatic cancer, especially when the clinical course and imaging findings are not helpful for differentiating them.
ABSTRACT
Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. Therefore, we investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct (EHBD) and GB. Activation of Notch signaling and oncogenic Kras resulted in the development of biliary intraepithelial neoplasia (BilINs) in the EHBD and GB, which were premalignant lesions that progressed to adenocarcinoma in mice. The expression of genes involved in the mTORC1 pathway was increased in biliary spheroids from Hnf1b-CreERT2; KrasLSL-G12D ; Rosa26LSL-NotchIC mice and inhibition of the mTORC1 pathway suppressed spheroid growth. Additionally, simultaneous activation of the PI3K-AKT and Notch pathways in EHBD and GB induced biliary cancer development in mice. Consistent with this, we observed a significant correlation between activated NOTCH1 and phosphorylated Ribosomal Protein S6 (p-S6) expression in human eCCA. Furthermore, inhibition of the mTORC1 pathway suppressed the growth of Notch-activated human biliary cancer cells in vitro and in vivo. Mechanistically, the Kras/Notch-Myc axis activated mTORC1 through TSC2 phosphorylation in mutant biliary spheroids. These data indicate that inhibition of the mTORC1 pathway could be an effective treatment strategy for Notch-activated human eCCA. © 2023 The Pathological Society of Great Britain and Ireland.
Subject(s)
Bile Duct Neoplasms , Biliary Tract Neoplasms , Carcinoma in Situ , Cholangiocarcinoma , Humans , Mice , Animals , Proto-Oncogene Proteins c-akt , Mechanistic Target of Rapamycin Complex 1 , Phosphatidylinositol 3-Kinases , Cholangiocarcinoma/pathology , Carcinoma in Situ/pathology , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathologyABSTRACT
The serrated neoplasia pathway constitutes an "alternative route" to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10-15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.
Subject(s)
Colonic Neoplasms , Colonic Polyps , Colorectal Neoplasms , Animals , Mice , Colonic Polyps/genetics , Colonic Polyps/pathology , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colonoscopy , Disease Progression , Tumor MicroenvironmentABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. We previously reported that chromatin remodeler Brg1 is essential for acinar cell-derived PDAC formation in mice. However, the functional role of Brg1 in established PDAC and its metastasis remains unknown. Here, we investigated the importance of Brg1 for established PDAC by using a mouse model with a dual recombinase system. We discovered that Brg1 was a critical player for the cell survival and growth of spontaneously developed PDAC in mice. In addition, Brg1 was essential for metastasis of PDAC cells by inhibiting apoptosis in splenic injection and peritoneal dissemination models. Moreover, cancer stem-like property was compromised in PDAC cells by Brg1 ablation. Mechanistically, the hypoxia pathway was downregulated in Brg1-deleted mouse PDAC and BRG1-low human PDAC. Brg1 was essential for HIF-1α to bind to its target genes to augment the hypoxia pathway, which was important for PDAC cells to maintain their stem-like properties and to metastasize to the liver. Human PDAC cells with high BRG1 expression were more susceptible to BRG1 suppression. In conclusion, Brg1 plays a critical role for cell survival, stem-like property and metastasis of PDAC through the regulation of hypoxia pathway, and thus could be a novel therapeutic target for PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Cell Proliferation , Hypoxia , Pancreatic Neoplasms/pathology , Animals , Mice , Pancreatic NeoplasmsABSTRACT
BACKGROUND: Breast cancer is highly heterogeneous, suggesting that small but relevant subsets have been under-recognized. Rare and mainly triple-negative breast cancers (TNBCs) were recently found to exhibit tuft cell-like expression profiles, including POU2F3, the tuft cell master regulator. In addition, immunohistochemistry (IHC) has identified POU2F3-positive cells in the normal human breast, suggesting the presence of tuft cells in this organ. METHODS: Here, we (i) reviewed previously identified POU2F3-positive invasive breast cancers (n = 4) for POU2F3 expression in intraductal cancer components, (ii) investigated a new cohort of invasive breast cancers (n = 1853) by POU2F3-IHC, (iii) explored POU2F3-expressing cells in non-neoplastic breast tissues obtained from women with or without BRCA1 mutations (n = 15), and (iv) reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from normal breast cells. RESULTS: Two TNBCs of the four previously reported invasive POU2F3-positive breast cancers contained POU2F3-positive ductal carcinoma in situ (DCIS). In the new cohort of invasive breast cancers, IHC revealed four POU2F3-positive cases, two of which were triple-negative, one luminal-type, and one triple-positive. In addition, another new POU2F3-positive tumor with a triple-negative phenotype was found in daily practice. All non-neoplastic breast tissues contained POU2F3-positive cells, irrespective of BRCA1 status. The scRNA-seq reanalysis confirmed POU2F3-expressing epithelial cells (3.3% of all epithelial cells) and the 17% that co-expressed the other two tuft cell-related markers (SOX9/AVIL or SOX9/GFI1B), which suggested they were bona fide tuft cells. Of note, SOX9 is also known as the "master regulator" of TNBCs. CONCLUSIONS: POU2F3 expression defines small subsets in various breast cancer subtypes, which can be accompanied by DCIS. The mechanistic relationship between POU2F3 and SOX9 in the breast warrants further analysis to enhance our understanding of normal breast physiology and to clarify the significance of the tuft cell-like phenotype for TNBCs.
Subject(s)
Carcinoma, Intraductal, Noninfiltrating , Triple Negative Breast Neoplasms , Female , Humans , Triple Negative Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Epithelial Cells/metabolism , SOX9 Transcription Factor/geneticsABSTRACT
RATIONALE: Pyomyositis is a microbial infection of the muscles and contributes to local abscess formation. Staphylococcus aureus frequently causes pyomyositis; however, transient bacteremia hinders positive blood cultures and needle aspiration does not yield pus, especially at the early disease stage. Therefore, identifying the pathogen is challenging, even if bacterial pyomyositis is suspected. Herein, we report a case of primary pyomyositis in an immunocompetent individual, with the identification of S aureus by repeated blood cultures. PATIENT CONCERNS: A 21-year-old healthy man presented with fever and pain from the left chest to the shoulder during motion. Physical examination revealed tenderness in the left chest wall that was focused on the subclavicular area. Ultrasonography showed soft tissue thickening around the intercostal muscles, and magnetic resonance imaging with short-tau inversion recovery showed hyperintensity at the same site. Oral nonsteroidal anti-inflammatory drugs for suspected virus-induced epidemic myalgia did not improve the patient's symptoms. Repeated blood cultures on days 0 and 8 were sterile. In contrast, inflammation of the soft tissue around the intercostal muscle was extended on ultrasonography. DIAGNOSES: The blood culture on day 15 was positive, revealing methicillin-susceptible S aureus JARB-OU2579 isolates, and the patient was treated with intravenous cefazolin. INTERVENTIONS: Computed tomography-guided needle aspiration from the soft tissue around the intercostal muscle without abscess formation was performed on day 17, and the culture revealed the same clone of S aureus. OUTCOMES: The patient was diagnosed with S aureus-induced primary intercostal pyomyositis and was successfully treated with intravenous cefazolin for 2â weeks followed by oral cephalexin for 6â weeks. LESSONS: The pyomyositis-causing pathogen can be identified by repeated blood cultures even when pyomyositis is non-purulent but suspected based on physical examination, ultrasonography, and magnetic resonance imaging findings.
Subject(s)
Pyomyositis , Staphylococcal Infections , Male , Humans , Young Adult , Adult , Pyomyositis/diagnosis , Pyomyositis/drug therapy , Abscess/microbiology , Cefazolin/therapeutic use , Staphylococcus aureus , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Anti-Bacterial Agents/therapeutic useABSTRACT
Fusobacterium nucleatum rarely causes vertebral osteomyelitis or liver abscesses, and no reports exist of it concurrently causing vertebral osteomyelitis and pyogenic liver abscess. A 58-year-old woman with a history of periodontitis presented with worsening lumbago, left lower leg pain, numbness, and fever for a week. Physical examination indicated knocking pain at the L2-L3 levels with a psoas sign on the left side. A magnetic resonance image showed L2-S1 vertebral osteomyelitis and intervertebral discitis, with a left psoas major muscle abscess. Vertebral osteomyelitis caused by Staphylococcus aureus was suspected; blood cultures were obtained, and intravenous cefazolin was administered. Computed tomography, which was performed to detect disseminated foci, revealed a multilocular liver abscess. On day 4 of incubation, the anaerobic blood culture bottles were positive for characteristic filamentous gram-negative rods. The empiric antimicrobial therapy was changed to ampicillin/sulbactam. The isolate was identified as F. nucleatum based on 16S rRNA gene sequencing. The liver abscess was drained on day 12. Based on the antimicrobial susceptibility test results, the patient was treated with intravenous ampicillin/sulbactam for 4 weeks followed by oral amoxicillin/clavulanate for an additional 8 weeks and remained disease-free at the 1-year follow-up. Clinicians should consider F. nucleatum as the causative organism for vertebral osteomyelitis presenting with asymptomatic pyogenic liver abscess. The gold standard for identifying and diagnosing F. nucleatum infections is 16S rRNA gene sequencing, and gram staining helps determine appropriate antimicrobials.