Identification of zinc finger MIZ-type containing 2 as an oncoprotein enhancing NAD-dependent protein deacetylase sirtuin-1 deacetylase activity to regulate Wnt and Hippo pathways in non-small-cell lung cancer.

BACKGROUND: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors. METHODS: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways. RESULTS: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear ß-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of ß-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified. CONCLUSIONS: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.

Sustained response following BTK inhibitors based treatment in HIV-related primary central nervous system lymphoma: case report.

BACKGROUND: Despite increasing effort for treating primary central nervous system lymphoma (PCNSL), the prognosis of human immunodeficiency virus (HIV) -related PCNSL was still unsatisfactory. There is currently a lack of clinical evidence for the application of Bruton tyrosine kinase (BTK) inhibitor in HIV-related PCNSL. We reported two HIV-related PCNSL patients, who achieved sustained remission by application of BTK inhibitor based treatment. This protocol had not been previously reported for the treatment of HIV-related PCNSL. CASE PRESENTATION: The two cases were characterized by the treatment choice of Bruton tyrosine kinase (BTK) inhibitor. Rituximab was not recommended for them due to their very low CD4+ T cell counts. They both took MTX as the first-line therapy and got a relief in initial phase. For the first case, ibrutinib was kept both in the first-line therapy and in the maintenance therapy. When the second case underwent a progressive disease, we continued to use orelabrutinib as one of the salvage treatment, in combination with programmed cell death-1 (PD-1) inhibitor plus lenalidomide. They both achieved a continuous response of up to 20 months without opportunistic infection. CONCLUSIONS: This report highlights the safety and effectiveness of BTK inhibitors, as well as lenalidomide and PD-1 inhibitor in HIV-related PCNSL patients. Both the new therapeutic approaches and a multidisciplinary team authentically contributed to improved survival outcome among HIV-positive PCNSL patients.

Ulcerative colitis complicated by primary sclerosing cholangitis and autoimmune hepatitis overlap syndrome: a case report and literature review.

Primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and ulcerative colitis (UC) are immune diseases of the digestive system. Some patients develop overlap syndrome, the presentation of two or more of the clinical, biochemical, immunological, and histological features of these conditions simultaneously or sequentially. The incidence of UC in PSC-AIH overlap syndrome is as high as 50%. In contrast, PSC-AIH overlap syndrome is rare in UC patients. However, because it has a low prevalence and has been studied in less detail, PSC is often misdiagnosed as primary biliary cholangitis (PBC) in its early stage. Herein, we reported a case of a 38-year-old male patient who presented to a clinician in 2014 with irregular bowel habits. A colonoscopy suggested UC. In 2016, the patient was found to have abnormal liver function and was diagnosed with PBC by pathology. He was treated with ursodeoxycholic acid (UDCA) but this had no effect on his liver function. Additional liver biopsies in 2018 indicated PBC-AIH overlap syndrome. The patient refused hormone therapy for personal reasons. Following UDCA monotherapy, his liver function remained abnormal. The patient was reexamined after repeated abnormal liver function tests and bowel symptoms. Systematic laboratory testing, imaging diagnosis, colonoscopy, liver biopsy, and various pathological examinations conducted in 2021 were used to diagnose the patient with PSC-AIH-UC overlap syndrome. He was treated with various drugs, including UDCA, methylprednisolone, mycophenolate mofetil, and mesalazine. His liver function improved significantly after treatment and follow-up is ongoing. Our case report highlights the need to raise awareness about rare and difficult-to-diagnose clinical disorders.

Tuberous Sclerosis Complex With Multiple Organ Tumors: Case Report and Literature Review.

Pancreatic neuroendocrine neoplasms (PNEN) are tumors that originate from neuroendocrine cells. Only about 1% patients are related to mutation of tuberous sclerosis complex gene. Here, we reported a rare case with involvement of multiple organs and space-occupying lesions. Initially, the patient was thought to have metastasis of a pancreatic tumor. However, the patient was diagnosed as pancreatic neuroendocrine tumors, liver perivascular epithelioid tumors, splenic hamartoma, and renal angiomyolipoma by pathological examination after surgery. We performed genetic mutation detection to identify that tuberous sclerosis complex 2 gene presented with a heterozygous variant. Tuberous sclerosis often presents with widespread tumors, but it is less common to present with pancreatic neuroendocrine tumors and liver perivascular tumors as highlighted in the case. So we analyzed the relationship between TSC gene mutations and related tumors. And we also reviewed the current molecular mechanisms and treatments for tuberous sclerosis complex.

Primary salivary gland-type polymorphous adenocarcinoma in the lung: A case report and literature review.

RATIONALE: Polymorphous low-grade adenocarcinoma is a low-risk infiltrative malignant tumor of the salivary glands. However, some of these tumors are more malignant than the low-grade tumors and therefore, according to the most recent recommendation of the World Health Organization, they are renamed as polymorphous adenocarcinomas (PACs). Primary polymorphous low-grade adenocarcinomas/PACs of the lungs are rare. Herein, we report a case of primary PAC of the lung with bronchial cartilage and perineural invasion, and lymph node metastasis. PATIENT CONCERNS: A 58-year-old man had developed fever half a month prior, without chills or other accompanying symptoms, and the underlying reasons were unknown. His self-measured temperature was up to 39°C, accompanied by cough and expectoration, yellow and thin sputum, and shortness of breath. The patient's general state was normal, and respiratory sounds originating from the right lung were weak. Enhancement computed tomography revealed that the bronchial lumen of the basal segment of the lower lobe of the right lung was narrow; soft tissue density nodules were seen, with a range of approximately 2.4 cm × 1.3 cm. DIAGNOSIS: Based on clinical information, morphological features, and immunohistochemistry results, the pathological diagnosis was primary PAC of the lungs. INTERVENTION: Thoracoscopic resection of the middle and lower lobes of the right lung was performed, further extended dissection of the mediastinal lymph nodes was performed. OUTCOMES: The postoperative course was uneventful. LESSONS: Primary PAC of the lung is rare and may cause misdiagnosis. When encountering a lung tumor with diverse tissue structures, uniform cell type and nerve invasion, we should consider the possibility of PAC. Morphological and immunohistochemical features can be useful for diagnosing primary PAC of the lungs.

IgG4-Related Disease With Gastrointestinal Involvement: Case Reports and Literature Review.

IgG4-related disease is an immune-mediated chronic, systemic, and autoinflammatory disease that can affect various organs throughout the body. The most commonly affected areas are the pancreas and biliary system. Due to the diverse clinical manifestations of the disease, it affects widely distributed organs. Thus, it is often easy to misdiagnose or miss. The digestive tract is a rarely affected system, and most IgG4-related gastric diseases manifest as tumors detected by endoscopy. This article reports two special cases with IgG4-related disease involving atrophic gastritis and intestinal polyps to provide a more empirical and theoretical basis for clinical diagnosis and treatment.

Multiple small bowel perforations due to cytomegalovirus related immune reconstitution inflammatory syndrome in an HIV patient: A case report.

RATIONALE: The presentation of multiple intestinal perforations is a severe complication of enteric cytomegalovirus (CMV) infection, sometimes associated with immune reconstitution inflammatory syndrome (IRIS) after the initiation of antiretroviral therapy (ART) in patients with human immunodeficiency virus (HIV). Here we reported a rare case of a patient with HIV infection who developed multiple perforations in the small bowel shortly after ART initiation without any prodromal gastrointestinal symptoms. We also reviewed the literature of reported cases to clarify their clinical characteristics for early diagnosis and rapid intervention. PATIENT CONCERNS: A patient with HIV presented with fever after 16 days of ART initiation and was admitted to our hospital. He was treated with intravenous ganciclovir due to persistent CMV viremia. The fever resolved 10 days later. However, he reported persistent left lower abdominal pain. DIAGNOSES: The patient was diagnosed with multiple small bowel perforations, CMV-related IRIS, and acquired immune deficiency syndrome. An upright abdominal x-ray in a tertiary level hospital revealed bilateral moderate intraperitoneal free air. We performed a pathological examination and metagenomic next-generation sequencing. CMV enteritis was confirmed by immunohistochemical staining and other opportunistic infections were excluded by metagenomic next-generation sequencing. INTERVENTIONS: The patient was treated with intravenous ganciclovir and 24 hours later, the patient underwent exploratory laparotomy. Partial resection and surgical repair of the small intestine were performed. OUTCOMES: The patient ultimately died from intestinal obstruction and septic shock 55 days after surgery. LESSONS: Perforations due to CMV-related IRIS are very rare, and usually appear shortly after ART initiation. Most cases lack the prodromal symptoms of abdominal pain and diarrhea. Intestinal perforations are lethal, and early detection and surgical treatment are lifesaving.

Case Report: SMARCB1 (INI-1)-Deficient Carcinoma of the Nasal Cavity with Pure Yolk Sac Tumor Differentiation and Elevated Serum AFP Levels.

In adults, yolk sac tumors (YSTs) in the nasal cavity and paranasal sinuses are very rare. To date, only six cases have been reported in the English literature. YSTs in adults are often accompanied by cancer, teratocarcinosarcoma, and other malignant components. Here, we have reported a case of nasal tumor in a 55-year-old man with nasal obstruction and epistaxis. Morphologically, the tumor showed histological characteristics of pure YST. Immunohistochemical staining showed diffuse expression of SALL4, CDX2, and GPC-3 accompanied by sporadic expression of alpha-fetoprotein (AFP) and CD117. After 20 and 40 days of operation, the serum AFP level was 220.30 and 43.60 ng/mL (normal, <7 ng/mL), respectively, which supported the pathological diagnosis of YST. However, we further performed immunohistochemical staining and fluorescence in situ hybridization using an INI-1 probe to detect the status of INI-1 in tumor cells. The results revealed that INI-1 was absent in tumor cells. Hence, we corrected the diagnosis to SMARCB1 (INI-1)-deficient carcinoma of the nasal cavity with YST differentiation. The patient underwent surgery and adjuvant radiotherapy in our hospital without evidence of recurrence or metastasis at the 6-month follow-up. The serum AFP level had also normalized. In conclusion, our case demonstrates that INI-1-deficient carcinoma may exhibit, a pure YST differentiation and immunophenotype, and elevated serum AFP levels. In adults, YST in the nasal cavity may represent INI-1-deficient carcinoma, which may be a potential diagnostic pitfall.

Thymic adenocarcinoma accompanied by type A thymoma and pulmonary minimally invasive adenocarcinoma and harboring distinct gene alterations: A case report.

RATIONALE: Thymic adenocarcinoma is an extremely rare thymic carcinoma. The exact genetic alteration associated with thymic adenocarcinoma is unclear. Here, we report a case of thymic adenocarcinoma accompanied by type A thymoma and pulmonary minimally invasive adenocarcinoma (MIA). PATIENT CONCERNS: A 53-year-old woman presented with multiple nodules in the mediastinum and lung. Thoracic computed tomography revealed nodules in the anterior superior mediastinum and anterior mediastinum near the right pericardium and ground-glass opacity (GGO) in the right superior lobe of the lung. DIAGNOSIS: The tumor in the anterior superior mediastinum was diagnosed as primary thymic papillary adenocarcinoma. The tumor in the anterior mediastinum near the right pericardium was diagnosed as type A thymoma. The GGO of the right superior lobe of the lung was diagnosed as a MIA. INTERVENTION: The patient underwent thoracoscopic mediastinal tumor resection and partial lobectomy in our hospital. OUTCOMES: The postoperative course was uneventful. The patient is alive and free of the disease for 22 months after diagnosis. LESSONS: Thyroid transcription factor 1 (TTF-1) was positive in this case of thymic adenocarcinoma, which indicated that a thymic adenocarcinoma with TTF-1-positive may not necessarily be a metastasis of lung or thyroid adenocarcinoma. The positive staining of CD5 and CD117 can help us to confirm the thymic origin. Molecular genetic analysis indicated that these tumors harbored different mutations. The thymic adenocarcinoma and type A thymoma both had the mutation of KMT2A, but the mutation sites were different. KMT2A mutation may be a common genetic change in thymic tumorigenesis. The genetic alterations disclosed in this study will help expand the understanding of thymic tumors.

WBP2 negatively regulates the Hippo pathway by competitively binding to WWC3 with LATS1 to promote non-small cell lung cancer progression.

WW domain binding protein-2 (WBP2) can function as a Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) co-activator and has a crucial role in promoting breast cancer progression. However, the expression and potential molecular mechanisms of WBP2 in the context of lung cancer are not fully understood. We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the advanced pTNM stage, lymph node metastasis, and poor prognosis of patients. In addition, gain- and loss-of-function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 (WW and C2 domain-containing-3) with LATS1 (Large tumor suppressor-1) through its PPxY motifs, thus inhibiting the formation of the WWC3-LATS1 complex, reducing the phosphorylation level of LATS1, suppressing the activity of the Hippo pathway, and ultimately promoting YAP nuclear translocation. Therefore, from the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.

Corrigendum: Gastric Cancer Cell-Derived Exosomal MicroRNA-23a Promotes Angiogenesis by Targeting PTEN.

[This corrects the article DOI: 10.3389/fonc.2020.00326.].

Appearance and morphologic features of laryngeal tuberculosis using laryngoscopy: A retrospective cross-sectional study.

ABSTRACT: Laryngeal tuberculosis (LTB) is highly contagious and can cause permanent laryngeal damage. Therefore, correctly identifying laryngoscopic LTB lesion locations, sizes, and morphologic features are essential for LTB diagnoses. This study aimed to explore the appearance and morphologic features of LTB and correlated these features with clinical symptoms.We retrospectively analysed 39 LTB patients in our hospital between January 2013 and December 2019. Medical records, including clinical presentation, lesion appearance (locations, sizes, and morphology), complementary examination results, and histopathologic features were summarized and analysed.In this patient cohort, dysphonia and sore throat were the two most common clinical symptoms. In LTB patients with extensive lesions, ulcerative lesions were most common, and the proportion of cases with concurrent pulmonary tuberculosis (86.4%, P = .033) infection was higher, as were the positive rates of sputum smears (72.7%, P = .011) and cultures (86.4%, P = .002) than patients without concurrent pulmonary TB and with more localized and exophytic lesions. The histopathologic features of LTB-related ulcerative lesions included fewer granulomas and more areas with caseous necrosis. These lesions were more likely to have acid-fast bacilli detected with a Ziehl-Neelsen stain than exophytic lesions that rarely showed detectable bacilli.A complete knowledge regarding the visual and morphologic features of LTB on laryngoscopy is needed for the early detection and diagnosis of LTB. Our study revealed the lesion sites, sizes, and morphologic features of LTB. These parameters were also correlated with patient clinical symptoms. Future studies are needed to support and expand the results of this retrospective study.

Immune reconstitution inflammatory syndrome associated with Pneumocystis pneumonia in a patient with AIDS.

Immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment for human immunodeficiency virus (HIV) infection has a wide variety of causes. Delayed diagnosis and treatment of IRIS is fatal. We report a case of a 21-year-old man with HIV infection and Pneumocystis jirovecii pneumonia. The patient presented with fever and dyspnea with deterioration of pulmonary infiltrations 5 days after starting antiretroviral treatment. We reached the diagnosis of IRIS based on radial endobronchial ultrasound (EBUS)-guided lung biopsy. In conclusion, radial EBUS-guided lung biopsy via bronchoscopy is a valuable and minimally invasive technique for the rapid diagnosis of IRIS-associated Pneumocystis jirovecii pneumonia.

LINC00858 knockdown inhibits gastric cancer cell growth and induces apoptosis through reducing WNK2 promoter methylation.

BACKGROUND: Emerging evidence indicates a regulatory role of long non-coding RNAs (lncRNAs) in the development of gastric cancer (GC), but the mechanisms underlying their function have remained largely unknown. Recent microarray-based expression profiling has led to the identification of a novel differentially expressed lncRNA, LINC00858, in GC. Subsequently, LINC00858 was found to be highly expressed in GC tissues and cells. This study was designed to clarify the functional role of LINC00858 in GC, including its effect on methylation of the WNK2 gene promoter and its downstream MAPK signaling pathway. METHODS: After exogenous over-expression and knockdown of LINC00858 and the addition of a MAPK pathway inhibitor in GC cells, we explored the effects of LINC00858 and the MAPK signaling pathway on GC cell behavior using various in vitro and in vivo assays. RESULTS: LINC00858 was found to negatively regulate WNK2 expression by enhancing its promoter methylation and to activate the MAPK signaling pathway. Moreover, we found that knockdown of LINC00858 or inhibition of the MAPK signaling pathway resulted in decreased GC cell growth, migration and invasion, as well as decreased cell cycle progression, along with increased apoptosis and decreased tumorigenicity. CONCLUSIONS: Together, these findings indicate that silencing of LINC00858 increases WNK2 expression and inhibits the MAPK signaling pathway, thereby inhibiting GC growth and development. Our data highlight LINC00858 as a potential target in GC therapy.

Gastric Cancer Cell-Derived Exosomal microRNA-23a Promotes Angiogenesis by Targeting PTEN.

Hypoxia-exposed lung cancer-released exosomal microRNA-23a (miR-23a) has been shown to enhance angiogenesis as well as vascular permeability, contributing to the close correlation between exosomal miR-23a and tumorigenesis. The current study aimed to investigate whether gastric cancer (GC) cell-derived exosomal miR-23a could induce angiogenesis and to elucidate the potential mechanisms associated with the process. Differentially expressed miRNAs in GC were initially screened from the Gene Expression Omnibus database. Target genes were selected following miRNA-mRNA prediction and subsequently verified by dual luciferase reporter assay. RT-qPCR was conducted to detect miR-23a and PTEN expression in GC tissues, cells and exosomes. Human umbilical venous endothelial cells (HUVECs) were co-cultured with GC cell-derived exosomes to assess the angiogenesis mediated by exosomes in vitro. Additionally, PTEN was overexpressed in HUVECs to analyze the mechanism by which miR-23a regulates angiogenesis. miR-23a was highly expressed in GC tissues and cells and GC cell-derived exosomes. Angiogenesis was promoted by the co-culture of HUVECs and GC cells-derived exosomes, as evidenced by the increased expression of VEGF but decreased expression of TSP-1. PTEN was targeted by miR-23a and was lowly expressed in GC tissues. In a co-culture system, miR-23a carried by GC cells-derived exosomes promoted angiogenesis via the repression of PTEN. Collectively, GC cell-derived exosomal miR-23a could promote angiogenesis and provide blood supply for growth of GC cells. This study contributes to advancement of miRNA-targeted therapeutics.

ANKHD1 promotes proliferation and invasion of non­small­cell lung cancer cells via regulating YAP oncoprotein expression and inactivating the Hippo pathway.

The ankyrin repeat and KH domain­containing 1 (ANKHD1) protein was recently reported to be a potential member of the Hippo signaling pathway. However, its role in human non­small­cell lung cancer (NSCLC) has not been extensively investigated. The aim of the present study was to examine the expression of ANKHD1 in primary human tissues and cells and determine whether it is correlated with the clinical characteristics of tumor growth. The biological functions of ANKHD1 were evaluated in vitro and in vivo. Yes­associated protein (YAP) expression and phosphorylation induced by ANKHD1 were evaluated by western blotting and immunoprecipitation. Marked upregulation of ANKHD1 protein expression was observed in NSCLC cells and tissues, which was associated with advanced pathological tumor­node­metastasis stage, lymph node metastasis and poor prognosis in patients with NSCLC. ANKHD1 overexpression also promoted the proliferation and invasion of NSCLC cells. ANKHD1 upregulation inactivated Hippo signaling via increasing YAP protein levels, as well as inhibiting YAP protein phosphorylation, whereas depletion of YAP abolished the effects of ANKHD1 on cell proliferation and invasion. Therefore, ANKHD1 may play an important role in NSCLC through regulating the YAP­dependent Hippo signaling pathway.