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MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
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Objective:To explore the effect of drug combined with CO2 laser minimally invasive surgery in the treatment of patients with vascularized vocal cord inflammation, and the influence on the voice function of patients.Methods:From April 2018 to July 2019, 74 patients with vascularized vocal cord inflammation admitted in the Affiliated Hospital of Yangzhou University were divided into two groups according to the random number table method, with 37 cases in each group.The patients in the control group were treated with oral medicine.The patients in the observation group were treated with medicine combined with CO 2 laser minimally invasive surgery.The voice quality, improvement of voice disorders, recurrence and patients' satisfaction were observed. Results:After treatment for 12 months, the total hoarseness(G), roughness(R) and breath(B) scores in the observation group were (1.60±0.13)points, (1.71±0.21)points and (1.42±0.12)points, respectively, which were significantly lower than those in the control group [(1.88±0.16)points, (1.98±0.10)points and (1.78±0.13)points] ( t=8.262, 7.061, 12.377, all P<0.05). After treatment, the functional, physiological and emotional scores of voice disorders index(VHI) and total score in the observation group were (10.10±1.03)points, (13.26±2.10)points, (7.30±1.10)points, (31.26±4.74)points, respectively, which were significantly lower than those in the control group [(11.63±2.16)points, (15.42±2.16)points, (8.86±1.05)points, (35.86±5.33)points] ( t=3.889, 4.361, 6.240, 19.103, all P<0.05). The recurrence rates at the first and third month after treatment in the observation group were 2.70%(1/37) and 8.11%(2/37), respectively, which were significantly lower than those in the control group [16.22%(6/37) and 27.03%(10/37)] (χ 2=3.945, 4.573, all P<0.05). The satisfaction rate of patients in the observation group was 94.59%(35/37), which was significantly higher than 78.38%(29/37) in the control group(χ 2=4.163, P<0.05). Conclusion:On the basis of conventional drug treatment, CO 2 laser microinvasive surgery can effectively improve the treatment effect, improve the voice function of patients, and significantly reduce the recurrence rate, the overall effect and prognosis are better.
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Objective To analyze the brain structure changes of the first-episode obsessive compulsive disorder (OCD) patients who were scanned by three-dimensional structure magnetic resonance imaging.Methods According to the diagnostic criteria of OCD in American Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-Ⅳ),the fist-episode obsessive compulsive disorder patients as case group(OCD,n=26) and the adult healthy volunteers as control group (control group,n=25) were selected.All subjects were assessed with Yale-Brown obsessive-compulsive scale(Y-BOCS),Hamilton Anxiety rating Scale (HAMA) and Hamilton Depression Rating Scale(HAMD),and then,they received 3D-MRI scanning runs.All the data was processed with freesurfer software and analyzed about cerebral cortical volume,cortical thickness,cortical surface area,the local gyrification index and subcortical nuclei volume.Results Compared with control group,the cerebral cortical thickness of OCD group increased at the left postcentral gyrus ((2.223±0.118)mm),left supramarginal gyrus ((2.486 ± 0.027) mm) and left parahippocampal gyrus ((2.399±0.164)mm).The cerebral cortical surface area larged at the right inferior frontal gyrus((1.036±0.079) mm2),right paracentral lobule ((0.827 ± 0.048) mm2) and medial orbitofrontal ((0.990 ± 0.083)mm2),and decreased at right superior parietal lobule ((0.779 ± 0.040) mm2),right inferior parietal lobule ((0.767±0.093) mm2) and right inferior temporal gyrus ((0.888±0.070) mm2).The cerebral cortical volume increased at the right inferior frontal gyrus((2.330±0.223) mm3).The cerebral cortical local gyrification index decreased at right middle temporal gyrus(2.893±0.288)and left inferior temporal gyrus(2.589±0.100).Conclusion The first-episode OCD patients have multiple changes of brain structures,and this changes were priority for the frontal lobes,orbital frontal,parietal lobe,temporal lobe and hippocampus.The changes in these regions maybe have close relationship with symptoms of OCD.
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Objective To investigate the anxiety condition of patients with benign paroxysmal positional vertigo (BPPV) and the relationship among the different genders, ages and education levels and anxiety.Methods The general information and a history of 58 patients diagnosed as BPPV were studied.State-trait anxiety inventory (STAI) was adopted to 58 cases of BPPV and compared with the Chinese standard norm.SPSS 19.0 software was used to analyze the data.Results There was no significant difference in trait anxiety (T-AI) score (Pm:0.539;Pf:0.924) between male and female patients with BPPV and the 1998 Chinese male and female norm.The S-AI scores were significantly higher in male and female BPPV patients than that in Chinese men and women norm scores (Pm:0.033;Pf:0.01).There was no significant difference in trait anxiety (T-AI) score (P:0.674;P:0.349;P:0.077) between patients with different genders, ages and education levels.There was significant difference in state anxiety (S-AI) score (P:0.046;P:0.02;P:0.035) between patients with different genders, ages and education levels.The anxiety degrees of BPPV in man, elderly people, higher degree of education were higher than those of in woman, young and middle-age, lower degree of education.Conclusion The patients with BPPV have anxiety condition, but there is no obvious anxiety potential in T-AI.The anxiety degree of BPPV in man, elderly people, higher degree of education was higher than those of in woman, young and middle-age, lower degree of education.Therefore, the correct psychological assessment and psychological intervention were required throughout the whole course of BPPV treatment and rehabilitation.
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Objective To explore the change rule of serum thyroid hormone level in senile patients. Methods Totally 2433 elderly patients in our hospital during January to August 2011 were divided into three groups by age:adult group aged(46.0± 10.8)years(n=1030),elderly group aged (69.5±6.3)years (n=848) and advanced age group aged (83.9±3.8)years (n=555).The levels of serum free triodothyronine (FT3),free thyroxine (FT4),thyroid-stimulating hormone (TSH) were determined by chemistry luminescence technique. Results The levels of serum FT3 [(4.33 ± 1.22)pmol/L,(3.96 ± 0.89) pmol/L vs.(5.08 ± 2.99) pmol/L,t=7.075,8.799,both P=0.000] and FT4 [(18.32±5.81)pmol/L,(18.58±6.71)pmol/L vs.(19.87±10.97) pmol/L,t=3.732,2.709,both P=0.000] were lower in the elderly and advanced age than in adult.The levels of serum TSH were higher in the elderly than in adult (P=0.002),while no difference was found between advanced age and adult (P=0.134)[(5.51± 17.39) mU/L in the elderly,(3.33±5.65) mU/L in adults vs.(4.53±14.37)mU/L in advanced age].There were no significant differences in the levels of serum FT3,FT4 and TSH between advanced age and the elderly (all P＞0.05).The detection rate of the decreased FT3,FT4 and TSH in elderly and advanced age were (13.3％ vs.25.8％),(2.9％vs.1.8％),(6.8％vs.12.3％),while the detection rate of increment were (3.1 ％vs.0.1％),(8.6％vs.9.9％),(18.0％vs.15.7％),respectively.The rates of declined FT3 and TSH were obviously higher in the advanced age than in the elderly (x2=39.96,15.83,all P =0.000),but the rates of declined FT4 and increased FT3 were lower in the advanced age than in the elderly (x2 =27.84,16.32,all P=0.000). Conclusions The abnormal detection rates of thyroid hormones are high in the elderly,thus due attention should be paid to thyroid function test for early diagnosis and treatment of senile thyroid disease.
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ObjectiveTo evaluate the value of inferior petrosal sinus sampling (IPSS) in the diagnosis of adreno-corticotropic hormone ( ACTH ) dependent Cushing syndrome ( CS ) with unknown origin. MethodsIPSS was carried out for the diagnosis of 16 cases with ACTH dependent CS who had not been identified after a series of dexamethasone suppression tests and radiological examinations. The ratio of inferior petrosal sinus/peripheral ACTH was assayed.The sensitivity and specificity of diagnosis of the Cushing disease were estimated. ResultsThe inferior petrosal sinus/peripheral ACTH ratio was over 2. 0 in 13 cases. Twelve cases underwent surgery with pathological diagnosis of pituitary ACTH adenoma, 1 patient relieved after γ knife treatment. The ratio was ＜ 2.0 in 3 cases including 2 pulmonary carcinoid and one pituitary ACTH adenoma. The sensitivity and specify of IPSS for the diagnosis of Cushing disease were 13/14and 2/2 respectively.ConclusionIPSS was a safe technique with high sensitivity, specify and infrequent complications in the diagnosis of ACTH dependent Cushing disease.It had great clinical value in the differential diagnosis of ACTH dependent Cushing disease with unknown origin.
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OBJECTIVE To understand the synaptic remodel in inner ear after hearing injury by investigating growth associated protein 43(GAP-43) expression in the inner ear hair cells after exposed Kangmin mice to neural injury noise stimulation to induce permanent threshold shift(PTS) or temporary threshold shift(TTS).METHODS To compare the expressions of GAP-43 of NMDAR signal pathway during neural injury stimulation by immunocytochemistry.RESULTS The sustained GAP-43 increase occurs after 7d and 14d of PTS group,and there is not remarkable difference between them.Compared with normal control,the change is not significant in TTS group.CONCLUSION The increase of GAP-43 in spiral ganglion after 7d trauma reveals the synaptic remodel in inner ear.
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Objective To analyze the central visual fields and the ocular fundus changes of both eyes of patients with pituitary adenoma. Methods A total of 70 cases of pituitary adenoma received the examination of static central visual fields of all liminal values by Humphrey instruments 750 cycloscope and the fundus exams by Topcon TRC 50X fundus photography before operations. Results There were 64.3% patients with decreased visual acuities, 80.7% with the defect of visual field, and 46.4% with fundus changes. The decrease of the visual acuity was the first diagnostic symptom in 45.7% patients, among whom 28.6% were misdiagnosed as ocular diseases. Conclusions The misdiagnosed cause is that the first diagnostic symptom is the decrease of visual acuity without defect of visual field accompanied by ocular diseases. To avoid the misdiagnosis and the omitter of pituitary adenoma, general examination of visual field should be carried out in the patients with decreased visual acuity and optic atrophy with unknown reason in the clinical diagnosis of ophthalmology.