RESUMO
BACKGROUND: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. METHODS: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. RESULTS: K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. CONCLUSIONS: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.
Assuntos
Queratina-17 , Neoplasias Pancreáticas , Humanos , Queratina-17/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/imunologia , Feminino , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Masculino , Linfócitos T CD8-Positivos/imunologia , Macrófagos/metabolismo , Macrófagos/imunologia , Pessoa de Meia-Idade , Idoso , Receptores de Superfície Celular , Antígenos de Diferenciação Mielomonocítica , Antígenos CDRESUMO
OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.
Assuntos
Biomarcadores Tumorais , Carcinoma Ductal Pancreático , Queratina-17 , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/diagnóstico , Biomarcadores Tumorais/metabolismo , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Idoso , Queratina-17/metabolismo , Queratina-17/genética , Fluoruracila/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Gencitabina , Imuno-Histoquímica , Adulto , Idoso de 80 Anos ou maisRESUMO
Background: The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. Methods: Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. Results: K17 expression had profound effects on the exclusion of intratumoral CD8 + T cells and was also associated with decreased numbers of peritumoral CD8 + T cells, CD16 + macrophages, and CD163 + macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8 + T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. Conclusions: Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.
RESUMO
OBJECTIVE: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. METHODS: We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity. RESULTS: We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues. CONCLUSIONS: Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias , Camundongos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Acetaminofen/efeitos adversos , Acetaminofen/metabolismo , Ácido Pirúvico/farmacologia , Alanina Transaminase , Estresse Oxidativo , Oxirredução , Glutationa/metabolismo , Alanina/farmacologiaRESUMO
BACKGROUND AND OBJECTIVES: Whole-body radiation exposure has been shown to alter the pharmacokinetics of certain drugs in both animal models and humans, but little is known about the effect of radiation on psychoactive medications. These drugs may have altered pharmacokinetics when administered during or after space travel or therapeutic or accidental radiation exposure, resulting in reduced efficacy or increased toxicity. METHODS: Methamphetamine was used to determine the effects of acutely administered 1, 3, and 6 Gy radiation on drug pharmacokinetics and pharmacodynamics. Male Wistar rats were exposed to 0, 1, 3, or 6 Gy X-ray radiation on day 0. The serum pharmacokinetics of subcutaneously administered 1 mg/kg methamphetamine was determined on day 3. Methamphetamine-induced (1 mg/kg) locomotor activity was measured on day 5. Brain methamphetamine concentrations were determined 2 h after methamphetamine administration (1 mg/kg) on day 6. Renal and hepatic serum biomarkers were assessed on days 3 and 6, with liver histology performed on day 6. RESULTS: While serum half-life and unchanged methamphetamine urine clearance were unaffected by any radiation dose, maximum methamphetamine concentrations and methamphetamine and amphetamine metabolite area under the serum concentration-time curve values from 0 to 300 min were significantly reduced after 6 Gy radiation exposure. Additionally, methamphetamine-induced locomotor activity and the brain to serum methamphetamine concentration ratio were significantly elevated after 6 Gy radiation. CONCLUSIONS: While 1-6 Gy radiation exposure did not affect methamphetamine elimination, 6 Gy exposure had effects on both subcutaneous absorption and brain distribution. These effects should be considered when administering drugs during or after radiation exposure.
Assuntos
Metanfetamina , Anfetamina/farmacocinética , Animais , Meia-Vida , Fígado , Masculino , Metanfetamina/farmacocinética , Ratos , Ratos WistarRESUMO
We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.
RESUMO
BACKGROUND: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ. METHOD: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of 2 biomarkers to VDZ was examined. RESULTS: Clinical response in UST was significantly higher than placebo (65% vs 39%; P = 0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs 20% (P = 0.02). For VDZ, clinical response with MVL of 1.35 to 1.55 µm was 82% vs 44% (<1.35 µm) and 40% (>1.55 µm; P = 0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis <14 positive cells/1000 IECs or MVL of 1.35 to 1.55 µm could identify 84% of responders and 67% of nonresponders (P = 0.001). CONCLUSION: Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, and combination of the 2 biomarkers enhanced the discriminate ability of responders from nonresponders to VDZ.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Biológicos , Doença de Crohn , Fármacos Gastrointestinais , Ustekinumab , Fatores Biológicos/uso terapêutico , Biomarcadores , Doença de Crohn/tratamento farmacológico , Células Epiteliais/citologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Estudos Prospectivos , Piroptose , Estudos Retrospectivos , Resultado do Tratamento , Ustekinumab/uso terapêuticoRESUMO
The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected 4 (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosylhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all 4 were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury, in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve preapproval drug safety assessment.
Assuntos
Alanina Transaminase/sangue , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Acetaminofen/toxicidade , Adenosil-Homocisteinase/metabolismo , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Dexametasona/farmacologia , Overdose de Drogas , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos WistarRESUMO
OBJECTIVE: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. DESIGN: Crohn's disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD). RESULTS: One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3-48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03-7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. CONCLUSIONS: Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Doença de Crohn/imunologia , Fármacos Gastrointestinais/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Mucosa Intestinal/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Colonoscopia , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Íleo/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudo de Prova de Conceito , Piroptose/efeitos dos fármacos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
We report a case of a 41-year-old male who presented to our institution with a large groin mass. CT, MRI and PET imaging was performed and was concerning for a soft tissue abscess likely originating in the lumbar spine. Differential considerations included infection, with atypical infections such as tuberculosis strongly considered. Biopsy revealed fungal elements preliminarily reported as consistent with Cryptococcus neoformans but later revealed to be Blastomyces dermatitidis. The patient responded positively following the introduction of appropriate treatment. This case illustrates the imaging similarities between spinal blastomycosis, spinal tuberculosis, and other fungal infections as well as the need for biopsy to differentiate.
Assuntos
Blastomicose/diagnóstico por imagem , Blastomicose/microbiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/microbiologia , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/microbiologia , Adulto , Antifúngicos/uso terapêutico , Blastomyces , Blastomicose/tratamento farmacológico , Diagnóstico Diferencial , Humanos , Masculino , Doenças da Coluna Vertebral/tratamento farmacológicoRESUMO
The use of prescription and over-the-counter medications is on the rise in the US population, especially among those aged 65 and over, with over 46% of the population taking at least 1 prescription medication. Given the frequency of medication use, and that the majority of these medications are taken orally, it has become increasingly relevant for pathologist examining endoscopically obtained gastrointestinal tract mucosal biopsies to consider and recognize patterns of mucosal injury associated with various drugs. Reports on injuries associated with certain classes of drugs can be scattered among different sources, making a comprehensive view of various injury patterns and the drugs known to cause them difficult to obtain. Herein, we provide a comprehensive overview of the drugs known to cause mucosal injuries in the tubular gastrointestinal tract organized by the organ involved and the prominent pattern of injury.
Assuntos
Mucosa Gástrica/patologia , Mucosa Intestinal/patologia , Medicamentos sem Prescrição/efeitos adversos , Medicamentos sob Prescrição/efeitos adversos , Biópsia , HumanosRESUMO
BACKGROUND: SMARCB1 (INI-1)-deficient sinonasal carcinoma (IDSNC) is a newly described, poorly differentiated carcinoma. Herein, the authors describe the cytopathologic features of IDSNC in fine-needle aspiration (FNA) samples. METHODS: The pathology archives of 2 academic institutions were searched for cases of IDSNC with available cytologic materials. All available slides were reviewed and a detailed morphological analysis was performed. RESULTS: Six cases were identified from 6 patients. FNA specimens were obtained from metastatic sites (4 cases), a local disease recurrence (1 case), and a primary lesion extending into the orbit (1 case). The majority of cases had cellular specimens with features of nonkeratinizing squamous cell carcinoma composed of cohesive clusters and sheets of oval to polygonal cells with indistinct cell borders present within a background of necrotic debris. Two cases had single rhabdoid cells with more abundant cytoplasm. The nuclei generally were small and uniform with fine chromatin, small nucleoli, and mild nuclear membrane irregularities; moderate anisonucleosis and multinucleation were noted in one case. Apoptotic bodies were common in 5 of 6 cases, and readily identifiable mitoses in 3 of 6 cases. Immunohistochemistry demonstrated that all cases expressed cytokeratins, 4 of 5 cases expressed p63, and all cases demonstrated loss of INI-1 nuclear expression. All cases were negative for neuroendocrine markers and aberrant p16 staining. CONCLUSIONS: A diagnosis of IDSNC can be suspected on FNA specimens from patients with high-grade sinonasal carcinomas that have either a nonkeratinizing squamous cell carcinoma or rhabdoid morphology. Clinical history and the availability of material for immunohistochemistry are key in confirming the diagnosis. Cancer Cytopathol 2018. © 2018 American Cancer Society.
Assuntos
Biomarcadores Tumorais/deficiência , Carcinoma de Células Escamosas/patologia , Citodiagnóstico/métodos , Recidiva Local de Neoplasia/patologia , Neoplasias dos Seios Paranasais/patologia , Proteína SMARCB1/deficiência , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biópsia por Agulha Fina , Carcinoma de Células Escamosas/genética , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Neoplasias dos Seios Paranasais/genética , Prognóstico , Estudos Retrospectivos , Proteína SMARCB1/genéticaRESUMO
Endoscopic mucosal biopsies of the ampulla of Vater (AmpBx) are obtained to histologically assess for dysplasia or carcinoma. However, biopsy material is often scant and a host of factors can induce histologic changes that pose diagnostic challenges. We sought to investigate observer variability in interpretation of AmpBx and the impact clinical data may have on diagnostic interpretation. Thirty-one cases from institutional archives were selected, including 12 cases of reactive atypia (RA), 8 indefinite for dysplasia (ID), and 11 showing low-grade dysplasia (LGD). Slides were independently reviewed at 3 time points with and without clinical information by 6 pathologists who categorized the biopsies RA, ID, or LGD. Following the reviews, intraobserver and interobserver agreement was assessed. Review of AmpBx without clinical data showed fair (κ, 0.27), poor (κ, 0.07), and good (κ, 0.42) interobserver agreement for diagnoses of RA, ID, and LGD, respectively. Interobserver agreement improved for LGD (κ, 0.66 and 0.73) when clinical information was provided; however, agreement remained fair for RA (κ, 0.4 and 0.42) and poor-to-fair for ID (κ, 0.17 and 0.25). When follow-up data were reviewed, all cases that reached unanimous agreement had that diagnosis substantiated by subsequent endoscopic or histologic findings. The same was true of 13 of 19 cases that reached majority consensus. Given the potential clinical consequences of these diagnoses combined with the significant intraobserver and interobserver variability found in this study, we conclude that better-defined diagnostic criteria and consensus reads on difficult cases would assist in the histologic assessment of these challenging cases.
Assuntos
Ampola Hepatopancreática/patologia , Mucosa Intestinal/patologia , Biópsia , Proliferação de Células , Endoscopia Gastrointestinal , Humanos , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis.Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts.Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1.Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186-96. ©2018 AACR.
Assuntos
Proteínas de Transporte de Cátions/metabolismo , Claudina-1/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Proteína da Zônula de Oclusão-1/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal , Xenoenxertos , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Transcrição GênicaRESUMO
We are describing an interesting case of two chronic liver diseases in a 48-year-old Chinese woman. While chronic hepatitis B is a common entity in Asia, the patient was later found to have active, asymptomatic primary biliary cirrhosis due to a persistently elevated alkaline phosphatase level after optimal hepatitis B virus DNA suppression on antiviral therapy. This report emphasizes the importance of keeping a high index of suspicion for another potential liver disease process even after a patient has been successfully treated for a primary liver condition. Clinical vigilance, especially in atypical clinical presentations, can result in early accurate diagnosis and prompt treatment.
RESUMO
Ciliated foregut cysts are extremely uncommon pancreatic cystic lesions, with-to the best of our knowledge-only five cases previously reported in the English literature. We report herein on a case of a ciliated foregut cyst of the pancreas connected with the duct of Wirsung. The magnetic resonance imaging, endoultrasonographic, and cytologic features are described and a brief review of literature is also presented.
Assuntos
Endossonografia , Imageamento por Ressonância Magnética , Cisto Pancreático/diagnóstico por imagem , Cisto Pancreático/patologia , Biópsia por Agulha Fina , Colangiopancreatografia por Ressonância Magnética , Meios de Contraste , Diagnóstico Diferencial , Feminino , Humanos , Aumento da Imagem , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Ultrassonografia DopplerRESUMO
PURPOSE: To report a novel surgical technique for lower eyelid involutional ectropion repair using a lateral tarsal strip and internal retractor reattachment procedure involving full-thickness eyelid sutures. METHODS: A retrospective review was performed of patients who underwent repair of involutional ectropion via lateral tarsal strip and internal retractor reattachment with full-thickness eyelid sutures by 1 surgeon. Patients having concomitant or previous eyelid surgical procedures were excluded. Collected data included patient demographics, surgical outcomes, and length of follow up. RESULTS: Forty-one lower eyelids of 31 patients with involutional ectropion underwent surgical repair. There were 17 men and 14 women in the age range of 69 to 92 years (mean age 82.2±5.9 years). Surgical sites included 22 right and 19 left lower eyelids. Follow up ranged from 1 to 48 months with an average of 5.9 months. Surgical success with anatomical correction of involutional ectropion was achieved in 39 of 41 eyelids (95.1%). There were no perioperative or postoperative complications. Two of 41 (4.9%) eyelids had recurrence of ectropion 7 and 18 months after the procedure. CONCLUSIONS: This procedure combining lateral tarsal strip with internal retractor reattachment involving full-thickness eyelid sutures effectively addresses horizontal eyelid laxity and tarsal instability, providing an effective technique to correct involutional ectropion of the lower eyelid.
Assuntos
Ectrópio/cirurgia , Pálpebras/cirurgia , Músculos Oculomotores/cirurgia , Procedimentos Cirúrgicos Oftalmológicos , Técnicas de Sutura , Suturas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: To describe a novel technique for the surgical repair of involution entropion of the lower eyelid and to evaluate its effectiveness in a series of patients. METHODS: This retrospective interventional case series includes patients who underwent entropion repair via lateral tarsal strip with infraciliary rotation sutures during a 5-year period by one surgeon. Demographic data was collected and incidence of recurrence was determined. RESULTS: Forty-four eyelids of 36 patients with involutional entropion underwent surgical repair via lateral tarsal strip plus infraciliary rotation sutures. All patients had successful repair of entropion with no recurrences recorded on follow-up, which ranged from 1 to 67 months. CONCLUSIONS: Lateral tarsal strip combined with infraciliary rotation sutures is a successful method for the repair of involution entropion of the lower eyelid.
Assuntos
Entrópio/cirurgia , Técnicas de Sutura , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Suturas , Resultado do TratamentoRESUMO
Congenital blepharoptosis presents within the first year of life either in isolation or as a part of many different ocular or systemic disorders. Surgical repair is challenging, and recurrence necessitating more than one operation is not uncommon. Not all patients with congenital ptosis require surgery, but children with amblyopia due to astigmatic anisometropia or deprivation may benefit from early surgical correction. A variety of surgical procedures to correct congenital ptosis have been described. The choice of procedure depends on a number of patient-specific factors, such as degree of ptosis and levator function, as well as surgeon preference and resource availability. We review the genetics, associated syndromes, and surgical treatments of congenital ptosis.