Anti-neutrophil cytoplasmic antibody-associated hypertrophic cranial pachymeningitis and otitis media: a review of literature.

BACKGROUND AND OBJECTIVE: It has been recognized that anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides may lead to hypertrophic pachymeningitis (HP) or intractable otitis media (OM). To our knowledge, few cases of coexistent ANCA-related HP and OM have been described previously. To increase awareness of this disease, we reviewed the literature describing patients with HP and intractable OM in a population with AAV to guide clinical decision making for otolaryngologists. METHODS:  PubMed was searched with the following terms: ANCA-associated vasculitis, otitis media, and hypertrophic pachymeningitis. Only patients with concomitant AAV, OM and HP were considered and included in this review. RESULTS: A total of 243 articles were reviewed, and of these, 6 met inclusion criteria. Headache, cranial polyneuropathy, and intractable OM with effusion or granulation were common. Serum MPO-ANCA positivity was most common in Asian patients. Almost all patients had dural mater thickening on gadolinium-enhanced magnetic resonance imaging of the brain. Corticosteroids plus an immunosuppressant was more effective and most patients had improved hearing after treatment, but approximately 50% of subjects had disease relapse. CONCLUSION: In this review, we summarized the current knowledge on the clinical features, diagnosis, treatment, and pathogenesis of this disease. We should carefully detect the potential cases of ANCA-related HP and OM in patients with intractable OM, HP, or AAV, and make the optimal treatment plan to avoid long-term neurological complications and irreversible hearing loss. Furthermore, due to an increased possibility of relapse, close follow-up, including a hearing test, ANCA titers, imaging examination, and detection of toxic and side effects of immunosuppressive therapy, are necessary.

[Clinical and genetic diagnosis in a hereditary hemorrhagic telangiectasia family].

OBJECTIVE: To investigate the clinical features and feasibility genetic diagnosis in a hereditary hemorrhagic telangiectasia (HHT) family, and to explore the application of gene mutation testing in HHT diagnosis.
 Methods: Medical histories and clinical features of a family were analyzed to diagnose HHT patients and suspected individuals according to the clinical diagnostic criteria. Sequence analysis of endoglin (ENG) and activin A receptor like type 1 (ACVRL1) gene in the proband was performed with PCR and Sanger sequencing technology. After the possible pathogenic mutation was identified in the proband, the specific mutation was detected in the suspected individuals and part of other family members. Then the genetic diagnoses were concluded.
 Results: There were 5 family members in 4 generations manifested with epistaxis. According to the clinical diagnosis criteria, the proband with epistaxis, mucocutaneous telangiectases, visceral arteriovenous malformation and family history was diagnosed as HHT; while 2 survival family members with epistaxis and family history were suspected individuals. A substitution mutation in the 5'-untranslated region(5'-UTR) of ENG c.1-127 C>T was detected in the proband and the 2 suspected individuals, which did not exist in other family members. Based on the clinical and genetic findings, the 2 clinically suspected individuals were diagnosed as HHT.
 Conclusion: There is great variability of the clinical manifestations among HHT patients. ENG c.1-127 C>T mutation is the possible pathogenic variant of the HHT family. A combination of clinical and genetic diagnosis could improve the diagnosis and treatment of HHT.

Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias.

Disrupting the methylation of telomeric silencing 1-like (DOT1L)-mediated histone H3 lysine 79 has been implicated in MLL fusion-mediated leukemogenesis. Recently, DOT1L has become an attractive therapeutic target for MLL-rearranged leukemias. Rigorous studies have been performed, and much progress has been achieved. Moreover, one DOT1L inhibitor, EPZ-5676, has entered clinical trials, but its clinical activity is modest. Here, we review the recent advances and future trends of various therapeutic strategies against DOT1L for MLL-rearranged leukemias, including DOT1L enzymatic activity inhibitors, DOT1L degraders, protein-protein interaction (PPI) inhibitors, and combinatorial interventions. In addition, the limitations, challenges, and prospects of these therapeutic strategies are discussed. In summary, we present a general overview of DOT1L as a target in MLL-rearranged leukemias to provide valuable guidance for DOT1L-associated drug development in the future. Although a variety of DOT1L enzymatic inhibitors have been identified, most of them require further optimization. Recent advances in the development of small molecule degraders, including heterobifunctional degraders and molecular glues, provide valuable insights and references for DOT1L degraders. However, drug R&D strategies and platforms need to be developed and preclinical experiments need to be performed with the purpose of blocking DOT1L-associated PPIs. DOT1L epigenetic-based combination therapy is worth considering and exploring, but the therapy should be based on a thorough understanding of the regulatory mechanism of DOT1L epigenetic modifications.

[Expression of proteinase TMPRSS3 in mouse cochlea].

OBJECTIVE: To observe the expression of proteinase transmembrane protease, serine 3 (TMPRSS3) in mouse cochlea, and to investigate the significance of TMPRSS3 in the inner ear. METHODS: The protein expression of TMPRSS3 in C57/BL mouse cochlea was identified and detected by immunohistochemistry and immunofluorescence. Different cochlear tissues, such as spiral ganglion neurons, corti organ, stria vascularis and so on, were separated to detect the gene expression of TMPRSS3 by real-time fluorescence quantitative polymerase chain reaction (qPCR). The cochlear tissues with different ages were collected and the expression of TMPRSS3 mRNA was detected by qPCR. RESULTS: TMPRSS3 was mainly expressed in the spiral ganglion neurons, and there was TMPRSS3 mRNA in the cochlea in groups with different age. The expression level of TMPRSS3 mRNA was much weaker. CONCLUSION: The distribution of TMPRSS3 was observed in many regions of the mouse cochlea, but mainly in the spiral ganglion neurons. This indicates that TMPRSS3 may be involved in the physiological functional regulation of the spiral ganglion neurons.

[Expression of TMPRSS3 in the rat cochlea following kanamycin ototoxicity].

OBJECTIVE: To establish the kanamycin-induced deafness model in SD rats, and to investigate the expression and significance of transmembrane protease, serine 3 (TMPRSS3) in the cochlea following kanamycin ototoxicity. METHODS: A total of 40 male SD rats were randomly divided into 4 groups. The experimental rats received intramuscular kanamycin sulfate for 3, 7, and 14 consecutive days, and the control group were treated with normal saline for 14 days. Auditory brainstem responses (ABR) were obtained before and after the kanamycin administration. The expression of TMPRSS3 in the cochlea was identified and detected by immunohistochemistry and Western blot. RESULTS: Kanamycin-induced deafness model in the SD rats was successfully established. ABR thresholds were increased and the expression of TMPRSS3 in the cochlea was reduced after the kanamycin injection (P<0.01). CONCLUSION: TMPRSS3 may play an important role in normal cochlea function and involve in the process of aminoglycoside antibiotics induced deafness.

Extramedullary plasmacytoma of the larynx: Literature review and report of a case who subsequently developed acute myeloid leukemia.

Extramedullary plasmacytoma (EMP) of the larynx is an extremely rare plasma cell neoplasm outside of the bone marrow, which has not been previously well characterized. A case of laryngeal EMP who developed acute myeloid leukemia (AML) following treatment is described in the present study, as well as an extensive review of the relevant literature. An electronic literature search was performed in PubMed and all pertinent case reports and series in the English language from 1948-October 2017 were identified. A total of 99 cases including the present case were available for review. The mean age of the included patients was 53 years. Supraglottis was the most frequently involved site. The most common treatment modality was radiotherapy alone (n=41; 43%), followed by a combination of surgery and radiotherapy, then surgery alone. However, for cases published in recent years, the most common treatment modality was surgically based treatment. Overall the treatment outcome was favorable, as a total of 84% of patients were alive after a mean follow-up of 60 months. However, EMP outcomes for patients with cervical lymphadenopathy or multiple sites involvement were unfavorable with >40% of patients relapsing or developing metastasis during the limited follow-up period. A total of 6 subjects developed multiple myeloma and 1 patient converted to AML. The present study provides important insights on the treatment of EMP, which is a rare disease. To the best of our knowledge, this is the first case report of a patient with laryngeal EMP who developed AML following treatment. It is recommended that secondary myeloid neoplasm should be considered besides multiple myeloma during the follow-up period.

(-)-Epigallocatechin-3-gallate protects cultured spiral ganglion cells from H2O2-induced oxidizing damage.

OBJECTIVE: Oxidants play an important role in many diseases, including hearing loss. We hypothesized that (-)-epigallocatechin-3-gallate (EGCG) would protect spiral ganglion cells (SGCs) from H2O2-induced oxidizing damage. MATERIAL AND METHODS: SGCs of postnatal day 1-3 mice were cultured in vitro. H2O2 and EGCG were used at various concentrations. The apoptotic rate of SGCs was evaluated using Hoechst 33 258 staining, and cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide method. Semi-quantitative reverse transcriptase polymerase chain reaction was used to observe manganese superoxide dismutase (MnSOD) gene expression of SGCs treated with H2O2 and EGCG. RESULTS: The viability of cultured SGCs was significantly decreased, and the apoptotic rate of SGCs significantly increased, at H2O2 concentrations > or = 50 microM compared with the control (p < 0.05). MnSOD gene expression was upregulated with increasing H2O2 concentration in cultured SGCs, while this upregulation was suppressed by EGCG. CONCLUSION: It is suggested that EGCG, as an antioxidant, significantly protects auditory neurons against H2O2-induced oxidative damage.

[Effect of EGCG on H2O2-induced MnSOD gene expression in cultured spiral ganglion cells].

OBJECTIVE: To investigate the influence of EGCG on H2O2-induced gene expression of manganese superoxide dismutase (MnSOD or SOD2) in cultured spiral ganglion cells (SGCs) in vitro. METHODS: SGCs were cultured in vitro, and H2O2 and/or EGCG in different concentrations were used. Semi-quantitative RT-PCR was applied to observe MnSOD gene expression in SGCs after H2O2 and EGCG treatment. RESULTS: The expression of MnSOD gene was up-regulated with the increase of the concentration of H2O2 in cultured SGCs, and MnSOD gene expression was significantly up-regulated at a dose of H2O2 > or =100 micromol/L. However, this up-regulation was suppressed after simultaneously treated with 100 microg/ml EGCG. CONCLUSION: EGCG suppresses H2O2-induced up-regulation of MnSOD gene expression in cultured SGCs by getting rid of oxygen free radicals, reinforcing the activity of antioxidant enzymes such as MnSOD, and protects cultured SGCs from H2O2-induced oxidizing damage.

miR-204 suppresses cochlear spiral ganglion neuron survival in vitro by targeting TMPRSS3.

Sensorineural hearing loss (SNHL) is the most common cause of hearing impairment. One of the essential steps to prevent progressive hearing loss is to protect spiral ganglion neurons (SGNs) from ongoing degeneration. MicroRNAs and TMPRSS3 (transmembrane protease, serine 3) have been reported to be involved in development of SGNs and genesis of SNHL. The aim of this study was to investigate the role of miR-204 and TMPRSS3 in SGNs. Effect of miR-204 on cell viability of SGNs was first examined using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Expression of TMPRSS3 in SGNs with or without addition of miR-204 was assessed by real-time PCR and western blot further. A luciferase reporter activity assay was conducted to confirm target association between miR-204 and 3'-UTR of TMPRSS3. Finally, role of TMPRSS3 on cell viability of SGNs was evaluated by transfection of TMPRSS3 siRNA. Cell viability of SGNs was suppressed by miR-204 in a concentration-dependent manner. Overexpression of miR-204 reduced expression of TMPRSS3 in SGNs at both mRNA and protein levels. Binding to the 3'-UTR of TMPRSS3 by miR-204 was identified by luciferase assay. Knockdown of TMPRSS3 by siRNA significantly inhibits cell viability of SGNs. miR-204 could be a potential therapeutic target in sensorineural hearing loss.

[Clinical analysis on extramedullary plasmacytoma in the upper airway].

OBJECTIVE: To investigate the clinical manifestation, treatment and prognosis of extramedullary plasmacytoma(EMP) in the upper airway, and to improve the diagnosis and outcome of EMP treatment. METHOD: Clinical data of 26 EMP cases were reviewed retrospectively, and then compared with multiple myeloma(MM) patients presenting with lesions in upper airway. RESULT: Of 26 cases, 9 cases with the tumors occurred in nasal cavities, 7 in nasal sinuses, 6 in pharyngeal, 4 in throat, mainly manifesting with local masses and relevant symptoms. The manifestations of clinical, endoscopy findings and pathologic results in EMP patients were not distinguishable from the lesions of MM patients, while MM patients often accompanied by other findings, such as anemia and bone damage. Involvement of neck lymph nodes was more common in MM patients than in EMP patients. Ten patients were treated with surgery, and 16 patients with surgery and radiotherapy. Of the seven EMP patients with involvement of neck lymph nodes, four patients received additional chemotherapy besides surgery and radiotherapy, and no local relapse and MM happened in them, while of the three patients only received surgery and radiotherapy, one local relapse were found and one progressed to MM. CONCLUSION: The diagnosis of EMPs mainly depends on pathological results. The judgment of pathologists and application of molecular biology technology are vital for the diagnosis of EMP in upper airway, and MM must be excluded very carefully in the diagnosis of EMP. Surgery combined with radiotherapy is the main treatment for EMP in the upper airway, and the prognosis is good but the follow-up should be taken. Besides surgery and radiotherapy, chemotherapy is beneficial for the EMP patients accompanied with lesions in neck lymph nodes.

Comparative proteomic analysis of secreted proteins from nasopharyngeal carcinoma-associated stromal fibroblasts and normal fibroblasts.

Since the concept of the secretome (ensemble of proteins secreted and/or shed from cells) was proposed, it has become an attractive and challenging proteomic technology in recent years. However, secretome analysis still faces some difficulties mainly related to sample collection and preparation. In the present study, we established a reliable method for extracting secreted proteins by ultrafiltration centrifugation and conducting secretomic analysis. Accumulating evidence suggests that carcinoma-associated stromal fibroblasts (CAFs) play an important role in cancer initiation and progression. To investigate the expression patterns of secreted proteins from fibroblasts and to identify the secreted proteins involved in nasopharyngeal carcinoma (NPC) carcinogenesis, we conducted comparative secretome analysis between CAFs and normal fibroblasts. After two-dimensional gel electrophoresis (2-D PAGE), 11 significant spots were differentially expressed and identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). These proteins may take part in the regulation of the tumor micro-environment through different processes. The expression level of galectin-1 in the CAF supernatant was also determined by ELISA. This study provides useful information and new clues for the further understanding of the regulatory mechanisms of CAFs in the NPC microenvironment.

[Study on the surgery treatments in patients with maxillary osteofibrous hyperplasia of bone].

OBJECTIVE: To explore the clinical features, diagnosis and the surgery therapy of maxillary fibrous hyperplasia of bone. METHOD: The clinical data of 37 cases with maxillary fibrous hyperplasia of bone from 1987-2006 years were retrospectively analyzed. 19 cases of male and 18 cases of female, their average age is 22.5 years (17-35 years). Twenty-one cases were operated by Caldwell-lud or lateral rhinotomy operation. After 1997, 16 cases were operated by Caldwell-lud operation with endoscopy so as to strip hyperplasia bone. RESULT: Thirty-six cases were cured within 2-4 years follow-up, 1 case was reoperated by Caldwell-lud operation with endoscopy after recurrence. The patients who received operation by Caldwell-lud operation with endoscopy had less symptoms in the inflation deformity of maxillofacial region and dysfunction of neighbouring structures than those who received traditional operation. CONCLUSION: The diagnosis can be made by history, signs and radiography. Caldwell-lud operation with nasal endoscopy is more effective treatment, and advocated in clinical practice.

[Clinical features and treatment of nasal mucosa-associated lymphoid tissue lymphoma].

OBJECTIVE: To explore the clinical features and treatment of nasal mucosa-associated lymphoid tissue lymphoma (MALTL). METHOD: The data of 11 patients with nasal MALTL were analyzed retrospectively during 9 years, including their clinical features and effectiveness of treatment. Nine cases were male and 2 female, their age arranged from 18 to 49 years with an average age of 39 years. All cases underwent endoscopic sinus surgery, and were diagnosed by HE staining and immunohistochemistry. After operation, 7 cases were cured with immunotherapy and antibiotic therapy. Other 4 patients were treated by chemotherapy, radiotherapy, immunotherapy and antibiotic therapy. RESULT: During follow up 6-36 months, 4 patients died and other 7 patients achieved complete remission. CONCLUSION: Clinical manifestations of nasal MALTL are not typical,which is apt to be misdiagnosed and mistreated. The suspected lesion tissues under endoscopy should be completely resected and submitted to pathology investigation. Nasal MALTL is a subtype of non-Hodgkin lymphoma which is characterized by occult onset, long course, slow progression and low cure rates in the advanced stage.

[Mutation screening in selected exons of myosin 7a gene in prelingual non-syndromic hearing impairment patients].

OBJECTIVE: To ascertain the frequency and characteristics of myosin 7a gene mutations in Chinese with prelingual nonsyndromic hearing impairment. METHODS: Most of cases were collected within Hunan province, including 31 sporadic congenital deaf patients and 65 patients from 34 hereditary prelingual deafness families, and 100 health individuals were used as control. Genomic DNA was extracted from the patients and subjected to the PCR to amplify selected exons of myosin 7a gene, and then the amplified products were screened for base variations by single strand conformational polymorphismanalysis (SSCP). The bands with abnormal conformation were sequenced to confirm the mutation. RESULTS: G to A substitution was detected at nucleotide 617 in exon 7 as hetrozygous state in two patients and was not found in unaffected members in their family. This mutation caused Arg206Gln within a highly conserved heptapeptide sequence of myosin 7a protein, and was close relevant to the prelingual nonsyndromic deafness. CONCLUSIONS: The Arg206Gln mutation in exon 7 of myosin 7a is possibly a novel mutation to cause prelingual nonsyndromic hearing impairment. Our results provide the evidence that exon 7 of Myosin 7a is a mutational hotspot region in genetic deafness.