Dystonia, spastic tetraplegia, and ataxia due to a novel mutation in the dynamin domain of OPA1.

Movement disorders manifest in various hereditary neurodegenerative diseases. We reported a young man who presented with progressive upper limb dystonia, spastic tetraplegia, and ataxia. Whole-exome sequencing (WES) revealed a novel variant, c.2357A > G, in the dynamin domain of OPA1. No mtDNA deletion was detected in muscle by long-range PCR. Atrophy and decreased glucose metabolism of the basal ganglia were discovered. Decreased mtDNA copy number, fragmented mitochondria, slightly impaired oxidative phosphorylation, and increased autophagy were detected in mutant fibroblasts. Evident oxidative phosphorylation impairment and mtDNA deletions were not involved in the pathogenicity of this mutation unlike mutations in the GTPase domain of OPA1.

Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease.

Background and Objectives: Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods: The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5' untranslated region of the NOTCH2NLC gene were evaluated in all patients. Results: In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70-525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = -0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test). Discussion: This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.

Autonomic dysfunction-dominant phenotype in a Chinese family with biallelic GGC repeat expansions in NOTCH2NLC.

The GGC repeat expansions in the NOTCH2NLC gene are associated with multiple neurodegenerative disorders. Herein, we report the clinical phenotype in a family with biallelic GGC expansions in NOTCH2NLC. Autonomic dysfunction was a prominent clinical manifestation in three genetically confirmed patients without dementia, parkinsonism, and cerebellar ataxia for > 12 years. A 7-T brain magnetic resonance imaging in two patients revealed a change in the small cerebral veins. The biallelic GGC repeat expansions may not modify the disease progression in neuronal intranuclear inclusion disease. Autonomic dysfunction-dominant may expand the clinical phenotype of NOTCH2NLC.

The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients.

Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole-exome sequencing, mitochondrial DNA sequencing and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were leukoencephalopathies related to NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%) and HTRA1 (5%). Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%) and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R and HTRA1.

Clinical and therapeutical significances of the cluster and signature based on oxidative stress for osteosarcoma.

BACKGROUND: It is of great clinical significance to find out the ideal tumor biomarkers and therapeutic targets to improve the prognosis of patients with osteosarcoma (OS). Oxidative stress (OXS) can directly target intracellular macromolecules and exhibit dual effects of tumor promotion and suppression. METHODS: OXS-related genes (OXRGs) were extracted from public databases, including TARGET and GEO. Univariate Cox regression analysis, Random Survival Forest algorithm, and LASSO regression were performed to identify prognostic genes and establish the OXS-signature. The efficacy of the OXS-signature was further evaluated by Kaplan-Meier curves and timeROC package. Evaluation of immunological characteristics was achieved based on ESTIMATE algorithm and ssGSEA. Submap algorithm was used to explore the response to anti-PD1 and anti-CTLA4 therapy for OS. Drug response prediction was conducted by using pRRophetic package. The expression values of related genes in the OXS-signature were detected with PCR assays. RESULTS: Two OXS-clusters were identified for OS, with remarkable differences of clusters presented in prognosis. Kyoto Encyclopedia of Genes Genomes (KEGG) analysis showed that differentially expressed genes (DEGs) between the OXS-clusters were significantly enriched in several immune-related pathways. Patients with lower OS-scores attained better clinical outcomes, and presented more sensitivity to ICB therapy. By contrast, OS patients with higher OS-scores revealed more sensitivity to certain drugs. Furthermore, critical genes, RHBDL2 and CGREF1 from the model, were significantly higher expressed in OS cell lines. CONCLUSIONS: Our study identified the clusters and signature based on OXS, which would lay the foundation for molecular experimental research, disease prevention and treatment of OS.

Novel mutations in HTRA1-related cerebral small vessel disease and comparison with CADASIL.

OBJECTIVE: There is evidence showing both heterozygous HTRA1 and homozygous HTRA1 mutations as causal for familial cerebral small vessel disease (CSVD). The clinical and neuroimaging signs of heterozygous HTRA1-related CSVD can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to characterize the genotypic and phenotypic features of HTRA1-related CSVD, and we compared the features of heterozygous HTRA1-related CSVD and CADASIL. METHODS: We carried out genetic sequencing in a series of unrelated patients with suspected familial CSVD from China. Clinical and imaging characteristics of heterozygous HTRA1-related CSVD and CADASIL were compared. RESULTS: We identified nine heterozygous HTRA1 mutations and one homozygous HTRA1 mutation, seven of which are novel. Compared with CADASIL, patients with heterozygous HTRA1-related CSVD had a higher proportion of spine disorders and a lower proportion of white matter hyperintensities involving the anterior temporal lobe (p < 0.001). INTERPRETATION: This study shows that most HTRA1-related CSVD patients in China carry heterozygous HTRA1 mutations. The specific extra-neurological features and neuroimaging features reveal informative differences between heterozygous HTRA1-related CSVD and CADASIL. We expand the mutational spectrum of HTRA1.

[Retracted] MicroRNA­664 targets paired box protein 6 to inhibit the oncogenicity of pancreatic ductal adenocarcinoma.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that several of the panels showing flow cytometric assay data in Figs. 2D, 5D and 6E, western blotting data featured in Fig. 7, and certain of the cell migration assay data panels included in Fig. 5E and F and Fig. 6G were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 54: 1884­1896, 2019; DOI: 10.3892/ijo.2019.4759].

Clinical Features and Genetic Spectrum of Patients With Clinically Suspected Hereditary Progressive Spastic Paraplegia.

Background and Purpose: A variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs. Methods: A total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses. Results: The mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28. Conclusion: Causative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs.

Genotypic and phenotypic characteristics of juvenile/adult onset vanishing white matter: a series of 14 Chinese patients.

BACKGROUND: Vanishing white matter (VWM) is one of the most prevalent leukoencephalopathies and is caused by recessive mutations in gene eIF2B1-5. The onset may vary from an antenatal disorder that is rapidly fatal to an adult-onset disorder with chronic progressive deterioration. METHODS: Based on a comprehensive study of 14 juvenile/adult patients diagnosed in our department as well as a review of 71 previously reported cases of genetically confirmed juvenile/adult-onset VWM since 2001, we attempted to delineate the clinical symptoms, disease evolution, episodic aggravation, associated symptoms, MRI findings and genotypic characteristics of adult VWM. RESULTS: The onset age of neuropsychiatric symptoms was 23.4 ± 10.6 years, and the mean follow-up time was 8.1 ± 4.8 years. Major clinical symptoms included headache, epilepsy, cognitive decline, cerebellar ataxia, and urinary disturbances. Episodic aggravation was found in 42.9% of the patients in our series. Molecular studies revealed fourteen novel missense mutations. Diffuse abnormal signals characterized by T1-weighted hypointensity and T2-weighted hyperintensity were observed in the supratentorial white matter. CONCLUSIONS: The symmetrical leukoencephalopathy must be considered in patients of any age with premature ovarian failure or optic neuropathy. The VWM disease spectrum consists of characteristic imaging findings in combination with extremely wide variability in VWM patients.

Orelabrutinib-bruton tyrosine kinase inhibitor-based regimens in the treatment of central nervous system lymphoma: a retrospective study.

BACKGROUND: Central nervous system lymphoma (CNSL) is an aggressive lymphoma. Orelabrutinib, an oral Bruton tyrosine kinase inhibitor, is a new treatment strategy for CNSL. This study aims to evaluate the efficacy and safety of orelabrutinib-based regimens in the treatment of patients with CNSL. METHODS: Twenty-three patients with CNSL were included in this retrospective study. All patients received the orelabrutinib-based regimen. Efficacy was evaluated based on investigators' assessment of overall response rate (ORR), complete response/unconfirmed complete response (CR/CRu), partial response (PR), stable disease (SD), progressive disease (PD), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The safety of orelabrutinib-based regimens has also been evaluated. RESULTS: A total of 17.39% of patients received orelabrutinib-based regimens for consolidation therapy, and 82.61% of patients for induction therapy (4 newly diagnosed CNSL, 15 relapsed/refractory CNSL). In the newly diagnosed CNSL group, the ORR was 100% (1 CR, 1 CRu, 2 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 100%, 100%, and 100%, respectively. Of the 15 relapsed/refractory CNSL patients, five therapy regimens were applied (orelabrutinib, n = 3; orelabrutinib/immunotherapy, n = 3; orelabrutinib/chemotherapy, n = 2; orelabrutinib/immunochemotherapy, n = 6; orelabrutinib/radiotherapy, n = 1). The ORR was 60.00% (4 CR, 5 PR). The 6-month DOR rate, 6-month PFS rate, and 6-month OS rate were 92.30%, 67.70%, and 70.00%, respectively. Twenty-one patients reported adverse events (AEs), and 6 patients experienced grade ≥ 3 AEs. CONCLUSION: Orelabrutinib-based regimens were efficacious and well-tolerated in patients with CNSL. These combined therapies offer a new potential therapeutic strategy for patients with CNSL.

Clinical and pathological study of SORD-related distal motor neuropathy caused by novel compound heterozygous mutations in a Chinese patient.

Sorbitol dehydrogenase (SORD) has been identified as the causative gene of autosomal recessive distal hereditary motor neuropathies (dHMN). Here, we describe a 25-year-old woman who presented with progressive weakness of both lower limbs for the previous 10 years. Electrophysiological results suggested only a reduction in the compound muscle action potential (CMAP) amplitude of both the tibial and left deep peroneal nerves and neurogenic changes in needle EMG. A heterozygous c.757delG variant with a splicing c.786 + 1 G>A variant in the SORD gene was identified. A sural nerve biopsy revealed slight axon separation from the myelin sheath and thin myelin sheaths in very few nerve fibres and thickening of the microvasculature basement membrane. Our study expands the pathological and mutation spectrum of the SORD-related neuropathy.

Two Novel Myelin Protein Zero Mutations in a Group of Chinese Patients.

Mutations in the myelin protein zero gene are responsible for the autosomal dominant Charcot-Marie-Tooth disease (CMT). We summarized the genetic and clinical features of six unrelated Chinese families and the genetic spectrum of Chinese patients with myelin protein zero (MPZ) mutations. Our study reports data from a group of Chinese patients consisting of five males and one female with the age of disease onset ranging from 16 to 55 years. The initial symptom in all the patients was the weakness of the lower limbs. Electrophysiological presentations suggested chronic progressive sensorimotor demyelinating polyneuropathy. Overall six mutations were identified in the cohort, including four known mutations [c.103G>T (p.D35Y), c.233C>T (p.S78L), c.293G>A (p.R98H), and c.449-1G>T], and two novel mutations [c.67+4A>G with a mild CMT1B phenotype, and (c.79delG) p.A27fs with a rapidly progressive CMT1B phenotype]. According to the literature review, there are 35 Chinese families with 28 different MPZ mutations. The MPZ mutational spectrum in Chinese patients is very heterogeneous and differs from that of Japanese and Korean individuals, although they do share several common hot spot mutations.

Fotemustine-based therapy in combination with rituximab as a first-line induction chemotherapy followed by WBRT for newly diagnosed primary central nervous system lymphoma: a prospective phase II trial.

OBJECTIVE: This study aimed to evaluate the safety, efficacy, and feasibility of the rituximab, fotemustine, pemetrexed, and dexamethasone (R-FPD) regimen followed by whole-brain radiotherapy (WBRT) for patients with primary central nervous system lymphoma (PCNSL). METHODS: A prospective, single-center phase II clinical trial was conducted. Patients with PCNSL newly diagnosed at the First Affiliated Hospital of Zhengzhou University between July 2018 and July 2020 were studied. The R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100 mg/m2 i.v. on D1), pemetrexed (600 mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1-5). Patients 60 years or younger who showed a complete response (CR) were treated with 23.4 Gy of WBRT after the end of chemotherapy; those older than 60 years with CR were treated with a wait-and-see approach; and those who did not show CR after the 4th cycle of chemotherapy were given salvage WBRT 30 Gy + local tumor field irradiation up to 45 Gy, regardless of age. RESULTS: A total of 30 patients were included. After 2 cycles, the objective response rate (ORR) was 96.5% (28/29, 1 CR, 27 PR, 0 SD, and 1 PD). After 4 cycles, the ORR was 73.1% (19/26, 11 CR, 8 PR, 4 SD, and 3 PD). After WBRT, the ORR was 90.9% (10/11, 7 CR, 3 PR, and 1 SD). The grade III and IV toxicity responses were mainly leukopenia (20.0%), thrombocytopenia (23.3%), and anemia (10.0%). CONCLUSIONS: Fotemustine-based therapy in combination with rituximab chemotherapy followed by WBRT can improve outcomes, providing ORR benefits and favorable tolerability in patients newly diagnosed with PCNSL.

Genotypic and Phenotypic Characteristics of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy from China.

BACKGROUND AND PURPOSE: Studies have shown characteristics of genotypes and phenotypes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to describe the clinical and genetic characteristics of and correlations between the genotypes and phenotypes observed in CADASIL in China on the basis of exon classification. METHODS: Consecutive Chinese patients with CADASIL were evaluated. The detailed clinical and genetic features of CADASIL patients were collected. Genotypic and phenotypic characteristics were compared among 3 CADASIL groups: group 1 included patients with NOTCH3 mutations in exons 3-4, group 2 included those with NOTCH3 mutations in exon 11, and group 3 included those with NOTCH3 mutations in other exons. RESULTS: A total of 46 patients with CADASIL were evaluated. A comparison of 3 groups with mutations in different NOTCH3 exons revealed that individuals with exon 11 mutations were diagnosed at the oldest age, had the lowest modified Rankin Scale (mRS) scores, and were most likely to have basal ganglia (BG) enlarged perivascular spaces (EPVS) > 20 and atrophy. There were no significant clinical or neuroimaging differences between patients with mutations in exons 3-4 and those with mutations in other exons. CONCLUSIONS: Clinical and neuroimaging features are different among Chinese patients with mutations in exons 3-4, exon 11, or other exons. Exon 11 showed characterized phenotype (the oldest age at diagnosis, the lowest mRS scores, and were most likely to have BG EPVS > 20 and atrophy), there were no significant differences between exons 3-4 and other exons.

Intracranial Large Artery Abnormalities and Association With Cerebral Small Vessel Disease in CADASIL.

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic arteriopathy, the classic feature of which is small vessel lesions. Studies on intracranial large arteries in CADASIL are not common. We aim to evaluate intracranial large arteries, describing the characteristics of large arteries in CADASIL and their association with cerebral small vessel associated lesions. Methods: Consecutive CADASIL patients from a single-center prospective cohort were analyzed. Brain magnetic resonance imaging and magnetic resonance angiography were performed to assess the intracranial large arteries and cerebral small vessels associated lesions' neuroimaging. Results: The study included 37 CADASIL patients. Of the patients, 28 of them (75.7%) had intracranial large artery abnormalities. Eighteen (48.6%) had congenital variations such as fenestration, vertebral artery (VA) hypoplasia and agenesis, or common trunk and fetus posterior cerebral artery. Seventeen (45.9%) had acquired anomalies such as arterial stenosis, prolongation, or tortuosity (seven of them had both congenital and acquired anomalies). CADASIL patients with anterior circulation middle cerebral artery (MCA) or internal cerebral artery (ICA) severe stenosis were more likely to have ipsilateral asymmetric white matter hyper-density (WMH) distribution. Patients with posterior circulation VA hypoplasia had a higher prevalence of posterior subcortical zone dominant WMH distribution. Conclusion: CADASIL patients can demonstrate various intracranial large artery abnormalities which might influence the development of microangiopathy. Assessment of great vessels seems essential in CADASIL.

Three novel mutations in a group of Chinese patients with X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease type1 (CMTX1) is the second most common hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 (GJB1) gene. Here, we report the clinical and genetic features of six unrelated Chinese patients with CMTX1, which were identified by genetic analysis. Among the 6 identified mutations, 3 were previously unknown (c.31A > T, c.42 C > G and c.423 del C). The six patients showed typical signs of CMT with a median age of onset of 16.5 years (range: 13-30). Sensorineural hearing loss was confirmed in the patient with the c.423 del C mutation. White matter lesions on brain magnetic resonance imaging (MRI) were observed in two patients. The three newly identified GJB1 mutations expand the clinical and mutational spectrum of CMTX1.

c-Myc mediated upregulation of long noncoding RNA SNHG12 regulates proliferation and drug sensitivity in natural killer/T-cell lymphoma.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes. The treatment of NKTCL requires intensive chemotherapy. Long noncoding RNAs (lncRNAs) have been implicated in many cancers, including NKTCL. The elucidation of the multidrug resistance (MDR) may greatly contribute to explore novel therapeutic strategies. Herein, we explored the roles and potential regulatory mechanism of lncRNAs small nucleolar RNA host gene 12 (SNHG12) in MDR of NKTCL. We found that SNHG12 was upregulated in NKTCL tissue sections, and its high expression was positively correlated with clinical grade of malignancy of NKTCL. c-Myc and SNHG12 expression was upregulated in NKTCL cell lines. c-Myc- and SNHG12 overexpression promoted proliferation and inhibited sensitivity to cisplatin (CDDP) in NK/T-cell lymphoma cell line YTS cells, and c-Myc and SNHG12-downregulation inhibited proliferation and enhanced sensitivity to CDDP in SNK-6 cells. Moreover, c-Myc- and SNHG12 overexpression increased Ki67 and P-gp expression in YTS cells, whereas c-Myc and SNHG12-downregulation reduced the Ki67 and P-gp expression in SNK-6 cells. Correlational analyses revealed that c-Myc expression was positively correlated with SNHG12 expression in NKTCL tissues. Mechanism research showed that SNHG12 was a direct transcriptional target of c-Myc and c-Myc promoted SNHG12 expression in NKTCL cell lines. Further research showed that SNHG12 overexpression reversed the effects of c-Myc downregulation on proliferation and sensitivity to CDDP in NKTCL cell lines. Taken together, our findings first report that c-Myc mediated upregulation of SNHG12 promotes proliferation and inhibits drug sensitivity in NKTCL, which provides new insights into the therapeutic target for NKTCL.

MicroRNA-664 targets paired box protein 6 to inhibit the oncogenicity of pancreatic ductal adenocarcinoma.

The abnormal expression of microRNAs (miRNAs or miRs) with oncogenic or tumor­suppressive roles in pancreatic ductal adenocarcinoma (PDAC) has been widely reported in recent years, and these dysregulated miRNAs are implicated in the formation and progression of PDAC. Therefore, an investigation into the functional roles of miRNAs in PDAC may facilitate the identification of effective therapeutic targets. miRNA­664 (miR­664) has been found to be aberrantly expressed and to play crucial roles in several human cancer types. However, the expression pattern and functional roles of miR­664 in the malignant capacity of PDAC have yet to be elucidated. In this study, the results revealed that miR­664 was clearly downregulated in PDAC tissues and cell lines. The low miR­664 expression was strongly associated with pathological T stage and lymph node metastasis of the patients with PDAC. Patients with PDAC with a low miR­664 expression had a poorer overall survival and a worse disease­free survival than those patients with a high miR­664 level. Functional experiments suggested that exogenous miR­664 expression suppressed the growth and metastasis of PDAC cells in vitro, whereas miR­664 downregulation exerted the opposite effects. In addition, miR­664 suppressed the tumor growth of PDAC cells in vivo. Mechanistically, paired box protein 6 (PAX6) was identified as a direct target gene of miR­664 in PDAC cells. Furthermore, PAX6 was upregulated in PDAC tissues, and its upregulation inversely correlated with miR­664 levels. Moreover, the silencing of PAX6 mimicked the effects of miR­664 upregulation in PDAC cells, and the recovered expression of PAX6 eliminated the effects of miR­664 on PDAC cells. Notably, miR­664 could inhibit the activation of PI3K/Akt pathway in PDAC cells in vitro and in vivo. Cumulatively, these results indicate an important role of the miR­664/PAX6 pathway in suppressing the aggressiveness of PDAC cells, suggesting that miR­664 may be an attractive therapeutic target for the treatment of patients with this fatal disease.