Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

A Proposed Algorithm for Managing Cerebral Proliferative Angiopathy.

OBJECTIVE: Cerebral proliferative angiopathy (CPA) is a rare disease, characterized by a large vascular nidus, diffuse angiogenesis, and intermingled normal brain tissue. Conservative treatment, endovascular intervention, indirect revascularization, and radiotherapy have been applied to treat this disease. However, some cases deteriorate even after non-conservative treatment, and there has been no standard of treatment for this disease so far. In order to build a better treatment strategy, we review literature, present our case and propose an algorithm for managing CPA. METHODS: Following the PRISMA principle, we systemically reviewed literature discussing CPA. A case successfully managed with multi-modal treatment is also illustrated. RESULTS: A total of 23 articles with 74 cases of CPA were found. Thirty-three patients received single-modal management. These 33 cases include 24 receiving endovascular intervention, 7 receiving indirect revascularization, and 2 receiving radiotherapy. Three of the 33 patients deteriorated clinically, and 1 expired. We present a 6-year-old boy with left hemispheric CPA receiving indirect revascularization, followed by 2 consecutive courses of stereotactic radiosurgery targeting arteriovenous shunts in the left basal ganglia and arteriovenous shunts around the olfactory groove. In the follow-up period of more than 4 years, good collateral formation, improved perilesional perfusion, CPA shrinkage, and symptom relief were all achieved. CONCLUSIONS: Based on our literature review and case, we propose an algorithm for the management of CPA and emphasize that multi-modal treatment is necessary for most CPA cases.

Methylation- and homologous recombination deficiency-related mutant genes predict the prognosis of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a lung cancer subtype with poor prognosis. We investigated the prognostic value of methylation- and homologous recombination deficiency (HRD)-associated gene signatures in LUAD. METHODS: Data on RNA sequencing, somatic mutations, and methylation were obtained from TCGA database. HRD scores were used to stratify patients with LUAD into high and low HRD groups and identify differentially mutated and expressed genes (DMEGs). Pearson correlation analysis between DMEGs and methylation yielded methylation-associated DMEGs. Cox regression analysis was used to construct a prognostic model, and the distribution of clinical features in the high- and low-risk groups was compared. RESULTS: Patients with different HRD scores showed different DNA mutation patterns. There were 272 differentially mutated genes and 6294 differentially expressed genes. Fifty-seven DMEGs were obtained; the top 10 upregulated genes were COL11A1, EXO1, ASPM, COL12A1, COL2A1, COL3A1, COL5A2, DIAPH3, CAD, and SLC25A13, while the top 10 downregulated genes were C7, ERN2, DLC1, SCN7A, SMARCA2, CARD11, LAMA2, ITIH5, FRY, and EPHB6. Forty-two DMEGs were negatively correlated with 259 methylation sites. Gene ontology and pathway enrichment analysis of the DMEGs revealed enrichment of loci involved in extracellular matrix-related remodeling and signaling. Six out of the 42 methylation-associated DMEGs were significantly associated with LUAD prognosis and included in the prognostic model. The model effectively stratified high- and low-risk patients, with the high-risk group having more patients with advanced stage disease. CONCLUSION: We developed a novel prognostic model for LUAD based on methylation and HRD. Methylation-associated DMEGs may function as biomarkers and therapeutic targets for LUAD. Further studies are needed to elucidate their roles in LUAD carcinogenesis.

Research Progress of Cancer Stem Cells in Uveal Melanoma.

Uveal melanoma is the most common malignant tumor in adult eyes, mostly in the choroid, but also in the iris and ciliary body. Distant metastasis is found in nearly half of the patients. Cancer stem cells are a kind of cells with the ability of self-renewal and multidirectional differentiation, which are related to tumor invasion and metastasis. Although the concept of cancer stem cells is relatively mature in other tumors, its existence and verification methods in uveal melanoma are still uncertain. A more in-depth understanding of cancer stem cells and their mechanism may reveal new strategies to treat uveal melanoma. This article reviews the concept of cancer stem cells and their research progress in uveal melanoma, including identification, probable markers, cancer stem cell targeted drug therapy and the controversies and prospects in this field.

Resolution of type I Chiari malformation and associated syringomyelia following intrathecal chemotherapy: case report.

Type I Chiari malformation (CM-I) consists of downward herniation of the cerebellar tonsils below the foramen magnum and often requires surgical decompression if symptomatic. Spontaneous resolution of CM-I is rare. We present a case of resolved CM-I without surgery in a 6-year-old boy with B-cell lymphoma who was diagnosed with CM-I during lymphoma staging. Cerebrospinal fluid cytology and brain MRI revealed negative CNS involvement but showed CM-I with tonsillar ectopia 19 mm below the foramen magnum. The patient underwent induction chemotherapy including 5 doses of intrathecal chemotherapy. Follow-up MRI demonstrated marked regression of CM-I to less than 6 mm in 3 months, and complete resolution of CM-I was observed in 2 years. To the best of our knowledge, this is the first case of resolved CM-I and syringomyelia following chemotherapy. In this case report, the authors summarize all of the clinical characteristics, the radiological appearance, and the potential causes of resolution based on a review of the literature and propose the mechanisms through which intrathecal chemotherapy contributed to the CM-I and syringomyelia resolution in the present case.

Higher concentration of serum C-terminal cross-linking telopeptide of type I collagen is positively related with inflammatory factors in postmenopausal women with H-type hypertension and osteoporosis.

OBJECTIVE: To investigate the changes of inflammatory factors and bone metabolism markers in postmenopausal women with H-type hypertension and to assess the relationship between them. METHODS: Postmenopausal women who were diagnosed with osteoporosis were selected as observation objects. Participants were divided into three groups: only osteoporosis group (osteoporosis group), hypertension combined with osteoporosis group (hypertension group), and H-type hypertension combined with osteoporosis group (H-type hypertension group). The changes in bone mineral density and bone metabolic markers (osteocalcin [OC], procollagen type I N-terminal propeptide (PINP), and C-terminal cross-linking telopeptide of type I collagen [CTX]) and inflammatory factors (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were compared among three groups. RESULTS: In the hypertension group and the H-type hypertension group, the bone mineral density of the lumbar spine (0.647 ± 0.038 vs 0.638 ± 0.034 vs 0.668 ± 0.047, P < 0.05) and the femoral neck (0.567 ± 0.047 vs 0.552 ± 0.053 vs 0.618 ± 0.059, P < 0.05) was significantly lower than that in the osteoporosis group. The concentrations of CTX (266.61 ± 64.65 vs 293.09 ± 72.34 vs 235.48 ± 62.85, P < 0.05), IL-6 (44.36 ± 6.45 vs 48.05 ± 8.04 vs 39.06 ± 7.95, P < 0.05) and TNF-α (30.53 ± 6.28 vs 34.52 ± 7.15 vs 28.66 ± 6.19, P < 0.01) in the hypertension group and in the H-type hypertension group were significantly higher than those in the osteoporosis group. The concentrations of OC (30.59 ± 6.43 vs 27.10 ± 6.51, P < 0.05) and PINP (36.36 ± 6.16 vs 33.16 ± 6.77, P < 0.05) in the H-type hypertension group were increased dramatically. The concentration of CTX was positively correlated with the concentration of IL-6 (r = 0.587, P < 0.01) and TNF-α (r = 0.474, P < 0.01) and negatively related with the concentration of OC (r = -0.591, P < 0.01) and PINP (r = -0.646, P < 0.01) and the bone mineral density of the lumbar spine (r = -0.470, P < 0.01) and the femoral neck (r = -0.509, P < 0.01). CONCLUSION: Higher concentration of serum CTX is found in postmenopausal women with H-type hypertension, which is positively correlated with inflammatory factors. Besides, H-type hypertension could further enhance the activity of osteoclasts and increase the expressions of inflammatory factors, resulting in the aggravation of osteoporosis.

The role of sacral laminoplasty in the management of spina bifida and sacral cystic lesions: case series.

OBJECTIVE: Although laminae are not viewed as essential structures for spinal integrity, in the sacrum the anatomical weakness and gravity makes it a vulnerable area for CSF accumulation and expansion. The congenital or postoperative defects of sacral laminae, such as in patients with spina bifida, make this area more susceptible to forming progressive dural ectasia, pseudomeningocele, or expansile arachnoid cyst (Tarlov cyst). In addition, adhesions between the dura and surrounding soft tissue after laminectomy can cause some local symptoms, which are difficult to relieve. The authors propose that sacral laminoplasty with titanium mesh can provide a rigid support and barrier to resolve these sacral lesions and local symptoms. METHODS: From January 2016 to December 2017, patients with progressive CSF-containing lesions in the sacral area and defective sacral laminae were included in the study. After repair of the lesion, the authors performed sacral laminoplasty with titanium mesh in each patient. Subsequently, the soft tissue and skin were closed primarily. RESULTS: A total of 6 patients were included. Four patients with repaired myelomeningocele had progressive dural ectasia. One patient with lipomyelomeningocele previously underwent detethering surgery and developed postoperative pseudomeningocele. One patient had a symptomatic Tarlov cyst. Four of these 6 cases presented with low-back pain and local tenderness. During follow-up, ranging from 13 to 37 months, all 6 patients experienced no recurrence of dural ectasia or pseudomeningocele and were free from local symptoms. CONCLUSIONS: Sacral laminoplasty with titanium mesh is a safe and effective procedure for treating progressive sacral dural ectasia and refractory pseudomeningocele, preventing CSF leakage as well as relieving local symptoms that may occur years after previous surgery for spina bifida.

Reoperation for growth hormone-secreting pituitary adenomas: report on an endonasal endoscopic series with a systematic review and meta-analysis of the literature.

OBJECTIVE Surgery is generally the first-line therapy for acromegaly. For patients with residual or recurrent tumors, several treatment options exist, including repeat surgery, medical therapy, and radiation. Reoperation for recurrent acromegaly has been associated with poor results, with hormonal control usually achieved in fewer than 50% of cases. Extended endonasal endoscopic approaches (EEAs) may potentially improve the results of reoperation for acromegaly by providing increased visibility and maneuverability in parasellar areas. METHODS A database of all patients treated in the authors' center between July 2004 and February 2016 was reviewed. Cases involving patients with acromegaly secondary to growth hormone (GH)-secreting adenomas who underwent EEA were selected for chart review and divided into 2 groups: first-time surgery and reoperation. Disease control was defined by 2010 guidelines. Clinical and radiological characteristics and outcome data were extracted. A systematic review was done through a MEDLINE database search (2000-2016) to identify studies on the surgical treatment of acromegaly. Using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, the included studies were reviewed for surgical approach, tumor size, cavernous sinus invasion, disease control, and complications. Cases were divided into reoperation or first-time surgery for comparative analysis. RESULTS A total of 44 patients from the authors' institution were included in this study. Of these patients, 2 underwent both first-time surgery and reoperation during the study period and were therefore included in both groups. Thus data from 46 surgical cases were analyzed (35 first-time operations and 11 reoperations). The mean length of follow-up was 70 months (range 6-150 months). The mean size of the reoperated tumors was 14.8 ± 10.0 mm (5 micro- and 6 macroadenomas). The patients' mean age at the time of surgery was younger in the reoperation group than in the first-time surgery group (34.3 ± 12.8 years vs 49.1 ± 15.7 years, p = 0.007) and the mean preoperative GH level was also lower (7.7 ± 13.1 µg/L vs 25.6 ± 36.8 µg/L, p = 0.04). There was no statistically significant difference in disease control rates between the reoperation (7 [63.6%] of 11) and first-time surgery (25 [71.4%] of 33) groups (p = 0.71). Univariate analysis showed that older age, smaller tumor size, lower preoperative GH level, lower preoperative IGF-I level, and absence of cavernous sinus invasion were associated with higher chances of disease control in the first-time surgery group, whereas only absence of cavernous sinus invasion was associated with disease control in the reoperation group (p = 0.01). There was 1 case (9%) of transient diabetes insipidus and hypogonadism and 1 (9%) postoperative nasal infection after reoperation. The systematic review retrieved 29 papers with 161 reoperation and 2189 first-time surgery cases. Overall disease control for reoperation was 46.8% (95% CI 20%-74%) versus 56.4% (95% CI 49%-63%) for first-time operation. Reoperation and first-time surgery had similar control rates for microadenomas (73.6% [95% CI 32%-98%] vs 77.6% [95% CI 68%-85%]); however, reoperation was associated with substantially lower control rates for macroadenomas (27.5% [95% CI 5%-57%] vs 54.3% [95% CI 45%-62%]) and tumors invading the cavernous sinus (14.7% [95% CI 4%-29%] vs 38.5% [95% CI 27%-50%]). CONCLUSIONS Reoperative EEA for acromegaly had results similar to those for first-time surgery and rates of control for macroadenomas that were better than historical rates. Cavernous sinus invasion continues to be a negative prognostic indicator for disease control; however, results with EEA show improvement compared with results reported in the prior literature.

Transorbital endoscopic eyelid approach for resection of sphenoorbital meningiomas with predominant hyperostosis: report of 2 cases.

Sphenoorbital meningiomas (SOMs) are slow-growing tumors that originate from the sphenoidal wing and are associated with visual deterioration, extrinsic ocular movement disorders, and proptosis caused by hyperostosis of the lateral wall of the orbit. In some cases, the intracranial component is quite small or "en plaque," and the majority of the symptoms arise from adjacent hyperostosis. Craniotomy has traditionally been the standard of care, but new minimally invasive multiportal endoscopic approaches offer an alternative. In the current study, the authors to present their experience with the transorbital endoscopic eyelid approach for the treatment of 2 patients with SOMs and sphenoid wing hyperostosis. Clinical and radiological data for patients with SOMs who underwent a transorbital endoscopic eyelid approach were retrospectively reviewed. Surgical technique and clinical and radiographic outcomes were analyzed. The authors report the cases of 2 patients with SOMs and proptosis due to sphenoid wing hyperostosis. One patient underwent prior craniotomy to debulk the intracranial portion of the tumor, and the other had a minimal intracranial component. Both patients were discharged 2 days after surgery. MR images and CT scans demonstrated a large debulking of the hyperostotic bone. Postoperative measurement of the proptosis with the aid of an exophthalmometer demonstrated significant reduction of the proptosis in one of the cases. Persistence of intraconal tumor in the orbital apex limited the efficacy of the procedure in the other case. A review of the literature revealed 1 publication with 3 reports of the transorbital eyelid approach for SOMs. No measure of relief of proptosis after this surgery had been previously reported. The transorbital endoscopic approach, combined with endonasal decompression of the medial orbit, may be a useful minimally invasive alternative to craniotomy in a subset of SOMs with a predominantly hyperostotic orbital wall and minimal intracranial bulky or merely en plaque disease. In these cases, relief of proptosis and optic nerve compression are the primary goals of surgery, rather than gross-total resection, which may have high morbidity or be unachievable. In cases with significant residual intraconal tumor, orbital bone removal alone may not be sufficient to reduce proptosis.

Is the chiasm-pituitary corridor size important for achieving gross-total resection during endonasal endoscopic resection of craniopharyngiomas?

OBJECTIVE Craniopharyngiomas arise from the pituitary stalk, and in adults they are generally located posterior to the chiasm extending up into the third ventricle. The extended endonasal approach (EEA) can provide an ideal corridor between the bottom of the optic chiasm and the top of the pituitary gland (chiasm-pituitary corridor [CPC]) for their removal. A narrow CPC in patients with a prefixed chiasm and a large tumor extending up and behind the chiasm has been considered a contraindication to EEA, with a high risk of visual deterioration and subtotal resection. METHODS A database of all patients treated in the authors' center (Weill Cornell Medical College, NewYork-Presbyterian Hospital) between July 2004 and August 2016 was reviewed. Patients with craniopharyngiomas who underwent EEA with the goal of gross-total resection (GTR) were included in the study. Patients with postfixed chiasm or limited available preoperative imaging were excluded. Using preoperative contrast-enhanced T1-weighted sagittal midline MR images, the authors calculated the CPC as well as the distance from the chiasm to the top of the tumor (CTOT). From these numbers, they calculated a ratio of the CPC to the CTOT as a measure of difficulty in removing the tumors through the EEA and called this ratio the corridor index (CI). The relationship between the CI and the ability to achieve GTR and visual outcome were measured. RESULTS Thirty-four patients were included in the study. The mean CPC was 10.1 mm (range 5.2-19.1 mm). The mean CTOT was 12.8 mm (range 0-28.3 mm). The median CI was 0.8; the CI ranged from 0.4 to infinity (for tumors with a CTOT of 0). Thirty-two patients had GTR (94.1%) and 2 had subtotal resection. The CPC value had no relationship with our ability to achieve GTR and no effect on visual or endocrine outcome. CONCLUSIONS EEA for craniopharyngioma is generally considered the first-line surgical approach. Although a narrow corridor between the top of the pituitary gland and the bottom of the chiasm may seem to be a relative contraindication to surgery for larger tumors, the authors' data do not bear this out. EEA appears to be a successful technique for the majority of midline craniopharyngiomas.

Do craniopharyngioma molecular signatures correlate with clinical characteristics?

OBJECTIVE Exome sequencing studies have recently demonstrated that papillary craniopharyngiomas (PCPs) and adamantinomatous craniopharyngiomas (ACPs) have distinct genetic origins, each primarily driven by mutually exclusive alterations: either BRAF ( V600E), observed in 95% of PCPs, or CTNNB1, observed in 75%-96% of ACPs. How the presence of these molecular signatures, or their absence, correlates with clinical, radiographic, and outcome variables is unknown. METHODS The pathology records for patients who underwent surgery for craniopharyngiomas between May 2000 and March 2015 at Weill Cornell Medical College were reviewed. Craniopharyngiomas were identified and classified as PCP or ACP. Patients were placed into 1 of 3 groups based on their genomic mutations: BRAF mutation only, CTNNB1 mutation only, and tumors with neither of these mutations detected (not detected [ND]). Demographic, radiological, and clinical variables were collected, and their correlation with each genomic group was tested. RESULTS Histology correlated strongly with mutation group. All BRAF tumors with mutations were PCPs, and all CTNNB1 with mutations and ND tumors were ACPs. Preoperative and postoperative clinical symptoms and radiographic features did not correlate with any mutation group. There was a statistically significant relationship (p = 0.0323) between the age group (pediatric vs adult) and the mutation groups. The ND group tumors were more likely to involve the sella (p = 0.0065). CONCLUSIONS The mutation signature in craniopharyngioma is highly predictive of histology. The subgroup of tumors in which these 2 mutations are not detected is more likely to occur in children, be located in the sella, and be of ACP histology.

Limitations of the endonasal endoscopic approach in treating olfactory groove meningiomas. A systematic review.

OBJECTIVE: To review current management strategies for olfactory groove meningioma (OGM)s and the recent literature comparing endoscopic endonasal (EEA) with traditional transcranial (TCA) approaches. METHODS: A PubMed search of the recent literature (2011-2016) was performed to examine outcomes following EEA and TCA for OGM. The extent of resection, visual outcome, postoperative complications and recurrence rates were analyzed using percentages and proportions, the Fischer exact test and the Student's t-test using Graphpad PRISM 7.0Aa (San Diego, CA) software. RESULTS: There were 444 patients in the TCA group with a mean diameter of 4.61 (±1.17) cm and 101 patients in the EEA group with a mean diameter of 3.55 (± 0.58) cm (p = 0.0589). GTR was achieved in 90.9% (404/444) in the TCA group and 70.2% (71/101) in the EEA group (p < 0.0001). Of the patients with preoperative visual disturbances, 80.7% (21/26) of patients in the EEA cohort had an improvement in vision compared to 12.83%(29/226) in the TCA group (p < 0.0001). Olfaction was lost in 61% of TCA and in 100% of EEA patients. CSF leaks and meningitis occurred in 25.7% and 4.95% of EEA patients and 6.3% and 1.12% of TCA patients, respectively (p < 0.0001; p = 0.023). CONCLUSIONS: Our updated literature review demonstrates that despite more experience with endoscopic resection and skull base reconstruction, the literature still supports TCA over EEA with respect to the extent of resection and complications. EEA may be an option in selected cases where visual improvement is the main goal of surgery and postoperative anosmia is acceptable to the patient or in medium-sized tumors with existing preoperative anosmia. Nevertheless, based on our results, it seems more prudent at this time to use TCA for the majority of OGMs.

Transtubular excisional biopsy as a rescue for a non-diagnostic stereotactic needle biopsy-case report and literature review.

Stereotactic needle biopsy, a standard of care for acquiring deep-seated pathology, has limitations and risks in some situations. We present an uncommon case with basal ganglia dematiaceous mycetoma. Due to the firm consistency of the lesion, the initial stereotactic needle biopsy failed to provide a diagnosis. In a second operation, transtubular excisional biopsy was successfully performed to remove the entire mycetoma. We reviewed recent case series of transtubular approaches to deep-seated brain lesions and suggest this method could be a rescue for a non-diagnostic stereotactic needle biopsy and even may be the approach of choice in some cases.

Predictors and incidence of orthostatic headache associated with lumbar drain placement following endoscopic endonasal skull base surgery.

BACKGROUND: Orthostatic headache (OH) is a potential complication of lumbar drainage (LD) usage. The incidence and risk factors for OH with the use of lumbar drainage during endoscopic endonasal procedures have not been documented. OBJECTIVE: To investigate the incidence of post-procedure OHs associated with placement of LD in patients undergoing endoscopic endonasal procedures. METHODS: We prospectively noted the placement of LDs in a consecutive series of endoscopic endonasal skull base surgeries. Charts were retrospectively reviewed, and patients were divided into two groups: those with OH and those without. The patient demographics, drain durations, imaging findings of intracranial hypotension, pathologies and need for a blood patch were compared between the two groups. RESULTS: Two hundred forty-nine patients were included in the study. Seven patients (2.8%) suffered post-dural puncture OH, which was mild to moderate and disappeared 2-8 days (median 3 days) after treatment. Blood patches were used in four patients. Significant predisposing factors were age (33.0 vs. 53.5, P = 0.014) and a strong trend for female gender (85.7% vs. 47.9%, P = 0.062). BMI and drain duration were not significant. Postoperative intracranial hypotension was diagnosed radiographically in 43% of OH patients and in 5.4% of those without OH (P = 0.003). Four (1.6%) patients required treatment with an epidural blood patch. CONCLUSION: OH associated with intracranial hypotension in patients undergoing endoscopic endonasal procedures with LDs is an infrequent complication seen more commonly in young female patients. Radiographic signs of intracranial hypotension are a specific but not sensitive test for OH.

DNA damage responsive miR-33b-3p promoted lung cancer cells survival and cisplatin resistance by targeting p21WAF1/CIP1.

Cisplatin is the most potent and widespread used chemotherapy drug for lung cancer treatment. However, the development of resistance to cisplatin is a major obstacle in clinical therapy. The principal mechanism of cisplatin is the induction of DNA damage, thus the capability of DNA damage response (DDR) is a key factor that influences the cisplatin sensitivity of cancer cells. Recent advances have demonstrated that miRNAs (microRNAs) exerted critical roles in DNA damage response; nonetheless, the association between DNA damage responsive miRNAs and cisplatin resistance and its underlying molecular mechanism still require further investigation. The present study has attempted to identify differentially expressed miRNAs in cisplatin induced DNA damage response in lung cancer cells, and probe into the effects of the misexpressed miRNAs on cisplatin sensitivity. Deep sequencing showed that miR-33b-3p was dramatically down-regulated in cisplatin-induced DNA damage response in A549 cells; and ectopic expression of miR-33b-3p endowed the lung cancer cells with enhanced survival and decreased γH2A.X expression level under cisplatin treatment. Consistently, silencing of miR-33b-3p in the cisplatin-resistant A549/DDP cells evidently sensitized the cells to cisplatin. Furthermore, we identified CDKN1A (p21) as a functional target of miR-33b-3p, a critical regulator of G1/S checkpoint, which potentially mediated the protection effects of miR-33b-3p against cisplatin. In aggregate, our results suggested that miR-33b-3p modulated the cisplatin sensitivity of cancer cells might probably through impairing the DNA damage response. And the knowledge of the drug resistance conferred by miR-33b-3p has great clinical implications for improving the efficacy of chemotherapies for treating lung cancers.

Identification of the lncRNA, AK156230, as a novel regulator of cellular senescence in mouse embryonic fibroblasts.

Long noncoding RNAs (lncRNAs) have gained extensive attentions in recent years because of their potential importance in a variety of biological and pathological processes. In this study, we sought to explore the role of lncRNAs in cellular senescence. Here, we report that the lncRNA AK156230 was downregulated during replicative senescence in mouse embryonic fibroblasts (MEFs), and knockdown of AK156230 promotes a robust senescence phenotype, including increase in the numbers of the senescence-associated ß-galactosidase-positive cells, decrease of cell proliferation, accumulation of cells in the G2/M phase and reduction of autophagic activity. The cells with knockdown AK156230 expression also exhibited increased levels of p21, p53 and phosphorylated p53, and a decreased activity of CDK1. Moreover, rapamycin-induced autophagy offered cytoprotective effect and rescued cellular senescence in AK156230 knockdown cells. Gene expression profile showed that the dysregulation of autophagy and cell cycle genes contributed to the induction of cellular senescence after AK1561230 silencing. Taken together, these results suggest that downregulation of AK156230 is involved in the induction of cellular senescence through its roles in autophagy and cell cycle progression. Our study identifies AK156230 as a critical lncRNA that has a role in regulating cellular senescence in MEFs.

The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population.

BACKGROUND: Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (≤ 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. METHODS: Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (≤ 60 years old) using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). CONCLUSIONS: Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects.

Construction of a high-quality genomic BAC library for Chinese peanut cultivar Zhonghua 8 with high oil content.

BACKGROUND: Arachis hypogaea L. (2n = 4× = 40, AABB) is one of the most important oil and economic crop plants in the word. This species has the largest genome size of about 2,813 Mb among the oil crop species. Zhonghua 8 is a peanut cultivar planted widely in central China and has several superior traits including high oil content, high yield and disease resistance. A high-quality BAC library of Zhonghua 8 was constructed for future researches on the genomics of Chinese peanut cultivars. RESULTS: A Hin d III-digested genomic BAC (bacterial artificial chromosome) library was constructed with the genomic DNA from leaves of Zhonghua 8. This BAC library consists of 160,512 clones and the average insert is estimated about 102 kb ranging from 30 to 150 kb. The library represents about 5.55× haploid genome equivalents, and provides a 99.71% probability of finding specific genes. The empty-vector rate is under 5 percent detected from 200 randomly selected clones. Probing of 384 clones with the psbA gene of barley chloroplast and the atp6 gene of rice mitochondrion indicated that the contamination with organellar DNA is insignificant. Successive subculture of three clones showed that the inserts are stable in one hundred generations. CONCLUSIONS: This study presented the construction of a high-quality BAC library for the genome of Chinese cultivated peanut. Many essential experiences were summarized in the present study. This BAC library can serve as a substantial platform for development of molecular marker, isolation of genes and further genome research.