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Cyclin-dependent kinase 9 (CDK9) inhibitors are a novel category of anticancer treatment for cancers. However, their effects on hepatocellular carcinoma (HCC) are rarely investigated. Human ribonucleotide reductase (RR, which consists of RRM1 and RRM2 subunits) catalyzes the conversion of ribonucleoside diphosphate into 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools, which play essential roles in DNA synthesis and DNA repair. In this study, we identified that CDK9 protein expression in adjacent non-tumor tissues predicted HCC patients' overall and progression-free survivals. The anticancer activity of a CDK9-selective inhibitor, LDC000067, on HCC cells was positively associated with its ability to inhibit the expression of RRM1 and RRM2. LDC000067 downregulated RRM1 and RRM2 expression through post-transcriptional pathway. Specifically, LDC000067 triggered RRM2 protein degradation via multiple pathways, including proteasome-, lysosome-, and calcium-dependent pathways. Furthermore, CDK9 positively correlates with RRM1 or RRM2 expression in HCC patients, and the expressions of these three genes were associated with the higher infiltration of immune cells in HCC. Taken together, this study identified the prognostic relevance of CDK9 in HCC and the molecular mechanism for the anticancer effect of CDK9 inhibitors on HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ribonucleótido Reductasas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Ribonucleótido Reductasas/genética , Quinasa 9 Dependiente de la Ciclina , Difosfatos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Línea Celular TumoralRESUMEN
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), an AIDS-defining cancer with abnormal angiogenesis. The high incidence of KS in human immunodeficiency virus (HIV)-infected AIDS patients has been ascribed to an interaction between HIV type 1 (HIV-1) and KSHV, focusing on secretory proteins. The HIV-1 secreted protein HIV Tat has been found to synergize with KSHV lytic proteins to induce angiogenesis. However, the impact and underlying mechanisms of HIV Tat in KSHV-infected endothelial cells undergoing viral lytic reactivation remain unclear. Here, we identified LINC00313 as a novel KSHV reactivation-activated long noncoding RNA (lncRNA) that interacts with HIV Tat. We found that LINC00313 overexpression inhibits cell migration, invasion, and tube formation, and this suppressive effect was relieved by HIV Tat. In addition, LINC00313 bound to polycomb repressive complex 2 (PRC2) complex components, and this interaction was disrupted by HIV Tat, suggesting that LINC00313 may mediate transcription repression through recruitment of PRC2 and that HIV Tat alleviates repression through disruption of this association. This notion was further supported by bioinformatics analysis of transcriptome profiles in LINC00313 overexpression combined with HIV Tat treatment. Ingenuity Pathway Analysis (IPA) showed that LINC00313 overexpression negatively regulates cell movement and migration pathways, and enrichment of these pathways was absent in the presence of HIV Tat. Collectively, our results illustrate that an angiogenic repressive lncRNA, LINC00313, which is upregulated during KSHV reactivation, interacts with HIV Tat to promote endothelial cell motility. These results demonstrate that an lncRNA serves as a novel connector in HIV-KSHV interactions.IMPORTANCE KS is a prevalent tumor associated with infections with two distinct viruses, KSHV and HIV. Since KSHV and HIV infect distinct cell types, the virus-virus interaction associated with KS formation has focused on secretory factors. HIV Tat is a well-known RNA binding protein secreted by HIV. Here, we revealed LINC00313, an lncRNA upregulated during KSHV lytic reactivation, as a novel HIV Tat-interacting lncRNA that potentially mediates HIV-KSHV interactions. We found that LINC00313 can repress endothelial cell angiogenesis-related properties potentially by interacting with chromatin remodeling complex PRC2 and downregulation of cell migration-regulating genes. An interaction between HIV Tat and LINC00313 contributed to the dissociation of PRC2 from LINC00313 and the disinhibition of LINC00313-induced repression of cell motility. Given that lncRNAs are emerging as key players in tissue physiology and disease progression, including cancer, the mechanism identified in this study may help decipher the mechanisms underlying KS pathogenesis induced by HIV and KSHV coinfection.
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VIH-1/fisiología , Herpesvirus Humano 8/fisiología , ARN Largo no Codificante/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Coinfección , Células Endoteliales/metabolismo , Perfilación de la Expresión Génica , Infecciones por VIH/virología , Humanos , Complejo Represivo Polycomb 2 , Sarcoma de Kaposi/virología , Activación Transcripcional , Regulación hacia Arriba , Activación Viral/genética , Replicación ViralRESUMEN
Alport syndrome (AS) is a progressive hereditary kidney disease characterized by hematuria, proteinuria, and progressive kidney dysfunction accompanied by sensorineural hearing loss and ocular abnormalities. Pathogenic COL4A3-5 variants can result in different AS spectra. Further, kidney cysts have been reported in adults with AS. However, the relationship between kidney cysts and AS remains unclear. Here, we report 3 cases of AS in children that occurred with kidney cysts. The patient in case 1 was initially diagnosed with IgA nephropathy at the age of 8 years but later developed bilateral multiple kidney cysts at the age of 17 years, suggesting autosomal-dominant polycystic kidney disease. Whole-exome sequencing identified a pathogenic COL4A5 variant and confirmed the AS diagnosis. The patients in cases 2 and 3 had already been diagnosed with X-linked AS using kidney biopsy and genetic analysis. Initial kidney ultrasonography showed nephromegaly; however, kidney cyst formation was observed during their annual follow-up. Our study supports the association between AS and kidney cysts. Kidney cysts in adolescents with suspected AS should not discourage clinicians from testing for pathogenic COL4A3-COL4A5 variants. Early detection of kidney cysts is critical because it may indicate kidney disease progression.
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Aggressive angiomyxoma (AAM) is a rare soft tissue tumor typically in the pelvis and perineum in women of reproductive age, which is easily misdiagnosed. We describe a woman with vulvar AAM, initially mismanaged as a Bartholin cyst. However, a huge pelvic mass is noted on the following imaging studies. The characteristics of AAM on computed tomography and magnetic resonance imaging have been specified in the literature, but we further point out the potential value of sonography in diagnosing AAM. Besides, excisional biopsy may cause tumor bleeding in a case of AAM.
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Mixoma/complicaciones , Mixoma/diagnóstico , Neoplasias Pélvicas/complicaciones , Neoplasias Pélvicas/diagnóstico , Neoplasias de la Vulva/complicaciones , Neoplasias de la Vulva/diagnóstico , Adulto , Femenino , Histocitoquímica , Humanos , Imagen por Resonancia Magnética , Microscopía , Mixoma/patología , Neoplasias Pélvicas/patología , Pelvis/diagnóstico por imagen , Pelvis/patología , Tomografía Computarizada por Rayos X , Ultrasonografía , Vulva/patología , Neoplasias de la Vulva/patologíaRESUMEN
Nasal extranodal NK/T-cell lymphoma (NNKTL) is a lethal disease due to poor prognosis with rapid progress. A 56-year-old man complained of left nasal obstruction and blood-stained nasal drip for two months. Incisional biopsies were performed at the outpatient department three times, and the diagnosis of SCC was made. The patient underwent wide excision of the entire lesion via endoscopic sinus surgery with navigation. Final pathologic report revealed NNKTL. Pathological examination of the tumor revealed overlying epithelium presenting as pseudoepitheliomatous hyperplasia (PEH), which mimicked SCC invasion, with infiltration of atypical lymphocytes in the deeper sections. Immunohistochemistry supported the diagnosis of NNKTL. Chemoradiotherapy was administered, and a complete response was achieved at the two-year follow-up. The correct diagnosis of NNKTL is essential for prompt treatment and prevention of superfluous surgery. Although the link between PEH and NNKTL may lead to a misdiagnosis of SCC, multiple large and deep biopsies can prevent this dilemma. A biopsy showing ulceration or necrosis can indicate PEH and imply potential malignancy. Repeated biopsies and complete immunohistochemical studies are important for diagnosing NNKTL.
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Kaposi sarcoma (KS) is a malignant vascular neoplasm caused by KS-associated herpesvirus (KSHV) infection. HIV plays a major role in KS pathogenesis. KS in HIV usually produces more malignant features than classic KS. Despite the close KS-HIV relationship, no study has reported the existence of HIV in KS tissue. We used ddPCR to detect HIV and KSHV in HIV+ KS samples and classic KS control. We verified KS cell types through immunohistochemistry and applied hypersensitive in situ hybridization (ISH) to detect HIV and KSHV in tumor cells. Furthermore, we co-stained samples with ISH and immunohistochemistry to identify HIV and KSHV in specific cell types. Regarding pathological stages, the KS were nodular (58.3%), plaque (33.3%), and patch (8.3%) tumors. Moreover, ddPCR revealed HIV in 58.3% of the KS samples. ISH revealed positive Pol/Gag mRNA signals in CD34 + tumor cells from HIV + patients (95.8%). HIV signals were absent in macrophages and other inflammatory cells. Most HIV + KS cells showed scattered reactive particles of HIV and KSHV. We demonstrated that HIV could infect CD34 + tumor cells and coexist with KSHV in KS, constituting a novel finding. We hypothesized that the direct KSHV-HIV interaction at the cellular level contributes to KS oncogenesis.
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Infecciones por VIH , Herpesvirus Humano 8 , Sarcoma de Kaposi , Neoplasias Cutáneas , Humanos , Sarcoma de Kaposi/complicaciones , Herpesvirus Humano 8/genética , Neoplasias Cutáneas/complicaciones , Infecciones por VIH/complicacionesRESUMEN
Neuroendocrine carcinomas (NECs) are poorly differentiated neuroendocrine tumors of the upper respiratory tract. We present an extremely rare case of nasopharyngeal large cell neuroendocrine carcinoma (LCNEC) synchronized with nasopharyngeal squamous cell carcinoma (SCC). Both SCC and LCNEC are associated with Epstein-Barr virus (EBV) infection, supported by the positive result of Epstein-Barr encoding region in-situ hybridization. Strong correlation is found between EBV infection and nasopharyngeal malignancies. Furthermore, the EBV status might be a crucial prognostic factor in nasopharyngeal LCNEC. EBV-positive LCNEC is effective to chemoradiotherapy, and may have preferable outcome than EBV-negative LCNEC arising in the nasopharynx or other sites. The recognition of the EBV status is important for patients to receive appropriate treatment.
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Trigeminal schwannomas are rare tumours comprising 0.2% of all intracranial tumours and 0.5% of all head and neck tumours. Patients with trigeminal schwannomas presented with facial hypoesthesia and pain. We presented a case with left bulging oropharynx. The CT scan showed a 3.8x2.6x4.9cm left parapharyngeal tumour compressed to the oropharynx and middle cranial fossa. We performed 3 ways in two times of operation to excise the whole tumour. We chose the transoral approach for parapharyngeal space, trans-parotid approach for deep parotid part and the endoscopic endonasal trans-pterygoid approach and trans-maxillary with Canine fossa trephination for intracranial lesions. The pathology showed schwannoma. A huge schwannoma extended from intracranial to several spaces is difficult to resect just by one approach. We should separate the tumour to several parts by clinical image before the operation and design a plan to remove the whole tumour in different approach. The different space of tumour involvement had several ways to access. We needed to choose the less harm but with better surgical field.
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BACKGROUND: Currently, there is no training model that simulates the target lesion encountered during endoscopic submucosal dissection. OBJECTIVE: To develop a novel method simulating a target lesion for endoscopic submucosal dissection. DESIGN: Training program with the use of an ex vivo porcine stomach model. SETTING: Clinical skills training center. INTERVENTION: A pseudopolyp was created by using an esophageal variceal ligation device to simulate a protruding (0-Ip) lesion, and the pseudopolyp was transected with a snare cautery to simulate a depressed (0-IIc) lesion. MAIN OUTCOME MEASUREMENTS: Evaluate the histological depth of the target lesions and resected specimens. RESULTS: Histological findings of the simulated targets showed artificial ulcerative or polypoid lesions involving the muscularis mucosa or superficial submucosa. The resected specimen was limited to the submucosal layer, and no perforation was noted. LIMITATIONS: Pilot study in an ex vivo porcine stomach model. CONCLUSION: The most important advantage of the model is to simulate realistic target lesions like those encountered in clinical practice in endoscopic submucosal dissection training. It allows trainees to practice how to make proper markings, delineate adequate safety margins, and properly manage different subtypes of early gastric cancer.
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Disección/educación , Educación de Postgrado en Medicina/métodos , Endoscopía Gastrointestinal/educación , Mucosa Gástrica/cirugía , Pólipos/cirugía , Animales , Humanos , Modelos Animales , PorcinosRESUMEN
Increasing evidence reveals that the Rho GTPase-activating protein is a crucial negative regulator of Rho family GTPase involved in tumorigenesis. The Rho GTPase-activating protein 25 (ARHGAP25) has been shown to specifically inactivate the Rho family GTPase Rac1, which plays an important role in pancreatic adenocarcinoma (PAAD) progression. Therefore, here we aimed to clarify the expression and functional role of ARHGAP25 in PAAD. The ARHGAP25 expression was lower in PAAD tissues than that in normal pancreatic tissues based on bioinformatics analysis and immunohistochemistry staining. Overexpression of ARHGAP25 inhibited cell growth of AsPC-1 human pancreatic cancer cells in vitro, while opposite results were observed in BxPC-3 human pancreatic cancer cells with ARHGAP25 knockdown. Consistently, in vivo tumorigenicity assays also confirmed that ARHGAP25 overexpression suppressed tumor growth. Mechanically, overexpression of ARHGAP25 inactivated AKT/mTOR signaling pathway by regulating Rac1/PAK1 signaling, which was in line with the results from the Gene set enrichment analysis on The Cancer Genome Atlas dataset. Furthermore, we found that ARHGAP25 reduced HIF-1α-mediated glycolysis in PAAD cells. Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD.
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Adenocarcinoma/genética , Carcinogénesis/genética , Proteínas Activadoras de GTPasa/genética , Regulación Neoplásica de la Expresión Génica , Proteína Oncogénica v-akt/genética , Neoplasias Pancreáticas/genética , Serina-Treonina Quinasas TOR/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Femenino , Proteínas Activadoras de GTPasa/biosíntesis , Glucólisis/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Experimentales , Proteína Oncogénica v-akt/biosíntesis , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/biosíntesisRESUMEN
BACKGROUND: This study assessed the performance of visceral adiposity index and body shape index in predicting diabetes mellitus (DM) risk and compared their predictive ability to that of body mass index and waist circumference. METHODS: Among 8249 consecutive subjects who attended the Nationwide Health Check Up System for Senior Citizens (≥ 65 years) between 2008 and 2018, we examined the associations of several adiposity indices with DM risk and explored gender differences. RESULTS: Among all adiposity indicators, Chinese visceral adiposity index (CVAI) demonstrated the highest discriminatory ability for diabetes mellitus with area under receiver operating characteristic curves (AUC) of 0.65, 0.68, and 0.66 for men, women, and all participants, respectively, and optimal cut-offs set as 126.09 in men and 117.77 in women. Compared with body shape index (ABSI), both CVAI and VAI were strongly associated with baseline DM (adjusted OR: 4.85, 95% CI: 4.05-5.82 and 4.22, 95% CI: 3.53-5.05 for 4th vs 1st quartile groups by CVAI and VAI, P < 0.001), which was more pronounced in older adult women (Pinteraction < 0.05). Over a median of 5.25 years (IQR: 3.07-6.44 years) follow-up, Cox regression models showed higher predictive ability of CVAI and VAI compared to ABSI. Further, both CVAI and VAI independently predicted new-onset DM (adjusted HR: 1.29, 95% CI: 1.22-1.37 and 1.16, 95% CI: 1.11-1.21 by CVAI and VAI) and composite endpoint of new DM and death among those without baseline DM. CONCLUSIONS: Our population-based data demonstrated that Chinese visceral adiposity index may serve as a superior clinical indicator of diabetes when compared with conventional anthropometric indices among older adult Chinese, especially in women.
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A 39-year-old female presented with abdominal distension. A right adnexal mass was found on physical examination, which was shown to be cystic on ultrasound. An exploratory laparotomy revealed a right ovarian mass, which was removed and a staging procedure was performed. Histologically, the mass was a borderline ovarian tumor with stromal microinvasion and hemangiomatous mural nodules.
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Adenocarcinoma Mucinoso/patología , Cistadenocarcinoma Mucinoso/patología , Hemangioma/patología , Neoplasias Ováricas/patología , Adenocarcinoma Mucinoso/cirugía , Adulto , Cistadenocarcinoma Mucinoso/cirugía , Femenino , Hemangioma/cirugía , Histocitoquímica , Humanos , Neoplasias Ováricas/cirugíaRESUMEN
The combined administration of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors might be considered as a treatment for poorly responsive cancer. We report a patient with brain metastatic lung adenocarcinoma in whom fatal myocarditis developed after sequential use of PD-1 and PD-L1 inhibitors. This finding was validated in syngeneic tumor-bearing mice. The mice bearing lung metastases of CT26 colon cancer cells treated with PD-1 and/or PD-L1 inhibitors showed that the combination of anti-PD-1 and anti-PD-L1, either sequentially or simultaneously administered, caused myocarditis lesions with myocyte injury and patchy mononuclear infiltrates in the myocardium. A significant increase of infiltrating neutrophils in myocytes was noted only in mice with sequential blockade, implying a role for the pathogenesis of myocarditis. Among circulating leukocytes, concurrent and subsequent treatment of PD-1 and PD-L1 inhibitors led to sustained suppression of neutrophils. Among tumor-infiltrating leukocytes, combinatorial blockade increased CD8+ T cells and NKG2D+ T cells, and reduced tumor-associated macrophages, neutrophils, and natural killer (NK) cells in the lung metastatic microenvironment. The combinatorial treatments exhibited better control and anti-PD-L1 followed by anti-PD-1 was the most effective. In conclusion, the combinatory use of PD-1 and PD-L1 blockade, either sequentially or concurrently, may cause fulminant cardiotoxicity, although it gives better tumor control, and such usage should be cautionary.
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Hernia Hiatal , Microcefalia , Nefrosis , Humanos , Hernia Hiatal/genética , Microcefalia/genética , Nefrosis/genéticaRESUMEN
BACKGROUND: Although propofol has been widely used the uncertainties about its pharmacokinetics and pharmacodynamics are still in existence especially on acute infusion model. This study was designed to observe the changes of the arterial and superior vena cava blood concentrations of propofol during cardiopulmonary bypass and to see whichever site is more appropriate for pharmacodynamic studies of propofol. METHODS: Eight patients undergoing cardiopulmonary bypass were infused rapidly with propofol. Samples were collected concurrently from bypass arterial side (Ca) and superior vena cava (Cv) side at 0, 0.5, 1, 1.5, 2, 5, 10, 20, 30, and 40 minutes after infusion and analyzed with high pressure liquid chromatography (HPLC). Arterial blood pressure was also recorded at the same time. RESULTS: After administration, the concentration at Ca side was significantly higher than that at the corresponding Cv side from 0.5 to 5 min. The concentration at Ca side peaked at 0.5 min, then decreased rapidly and crossed the Cv curve at approximately 10 min. Thereafter Cv side concentration was slightly higher than that of Ca side. The mean arterial blood pressure decreased significantly from 1 to 20 min after injection. The change in Cv side was significantly consistent with the blood pressure change in the distribution phase (r = 0.78, r2 = 0.61 P < 0.001) (0 to 5 min). CONCLUSIONS: There was a significant arteriovenous concentration difference of propofol after a rapid infusion in the cardiopulmonary bypass model. The hypotensive effect of propofol in the distribution phase can be predicted better on Cv side.
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Anestésicos Intravenosos/farmacología , Presión Sanguínea/efectos de los fármacos , Propofol/farmacología , Adulto , Anciano , Puente Cardiopulmonar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propofol/sangreRESUMEN
The primary neuroectodermal tumor of the ovary is extremely rare, and it manifests in 3 forms: differentiated, primitive, and anaplastic. The medulloblastoma belongs to the subgroup of primitive neuroectodermal tumor of the ovary. Only 3 cases of ovarian medulloblastoma have been reported in the literature, and all of them are presented without information about the specific pathological subtype. We present the fourth case of a 26-year-old woman who presented with abdominal fullness for months. Ultrasound exam showed a right adnexal mass with cystic feature and foci solid components. A partial oophorectomy was performed, and the mass was a desmoplastic medulloblastoma arising from an ovarian teratoma.
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Meduloblastoma/patología , Neoplasias Primarias Múltiples/patología , Tumores Neuroectodérmicos Periféricos Primitivos/patología , Neoplasias Ováricas/patología , Teratoma/patología , Adulto , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Meduloblastoma/metabolismo , Neoplasias Primarias Múltiples/metabolismo , Tumores Neuroectodérmicos Periféricos Primitivos/metabolismo , Neoplasias Ováricas/metabolismo , Teratoma/metabolismoRESUMEN
Lobar torsion after lung resection is a quite rare complication. A 50-year-old woman presented typical features on chest radiographs and CT(computed tomography) scan of lobar torsion after a right upper lobectomy. After emergency lobectomy of right middle lobe, the patient recovered well and discharged 10 days after the second operation.