Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

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.

PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.

Modified venous grafting to replant an amputated thumb with obstinate arteriospasm / 中华创伤骨科杂志

Objective To evaluate the therapeutic effects of bridging the proper digital artery and the radial artery with a vein graft in replantation of an amputated thumb with obstinate arteriospasm.Methods From June 2011 to May 2017,9 patients received replantation of an amputated thumb at Department of Hand Surgery,The Second Hospital of Tangshan.They were all male,aged from 21 to 55 years (average,39.2 years).Two right thumbs were involved in 2 cases and 7 left thumbs in 7 cases.During replantation,obstinate arteriospasm which could not be alleviated occurred of their bilateral proper digital arteries.A free forearm superficial vein graft was used to bridge the distal end of ulnar proper digital artery of thumb and the radial artery in tabatiere anatomique to establish blood supply by end-to-end or end-to-side anastomosis.At final follow-up,the outcomes were assessed by the tentative criteria set by The Hand Surgery Society of Chinese Medical Association.Results All the 9 replanted thumbs survived with primary wound healing.They were followed up for 6 to 12 months (mean,7.9 months).All the patients were satisfied with the appearance and function of the replanted thumb except that mild atrophy was observed in 2 digits with preoperative rotatory avulsion.According to the tentative criteria set by The Hand Surgery Society of Chinese Medical Association at final follow-up,the outcomes were rated as excellent in 7 cases and as good in 2.The pulp two-point discrimination was between 3 and 8 mm,with an average of 5.3 mm.Conclusions An amputated thumb with obstinate arteriospasm can be replanted by bridging the ulnar proper digital artery of thumb and the deep branch of radial artery using a vein graft to establish adequate blood supply to the replanted thumb,leading to satisfactory efficacy.As the technique is easy,it is worthy of popularization.

Comparing two surgical treatment methods for mucous cysts of the distal interphalangeal joint in elderly patients / 中华老年医学杂志

Objective To contrast and compare two surgical treatments for mucous cysts of the distal interphalangeal joint.Methods Clinical data from April 2004 to January 2016 were retrospectively analyzed.Patients who underwent tumor excision,osteophyte excision,and local flap coverage were assigned into a flap group(n=16),while patients who received osteophyte excision,cyst pedicle resection,and cystic fluid drainage were assigned into a simple osteophyte resection group(n=17).Procedure time,pain,satisfaction score,and hand function were compared between the two groups.Results Patients in the flap group were followed up for 14 to 28 months(mean=19.5 months);the simple osteophyte resection group for 15 to 26 months(mean=20.5 months).There was no recurrence in either group.The rate of excellent efficacy was 81.25 ％ (13/16)for the skin flap group and 82.35 ％ (14/17) for the simple osteophyte resection group,and the difference was not statistically significant(x2=0.007,P ＞ 0.05).Pain relief was achieved in both groups after operation,and the postoperative satisfaction score was higher than the pre-operation score.There was no statistical difference in pre operation pain and satisfaction scores (t 0.14 and 0.35,both P ＞ 0.05),no statistical difference in postoperative pain scores(t =-0.09,P ＞ 0.05),but a statistically significant difference in postoperative satisfaction scores (t =-4.15,P ＜ 0.05) between the two groups.Conclusions Two surgical treatments of mucous cysts can achieve satisfactory aesthetic and clinical outcomes.The simple osteophyte resection method is characterized by a short procedure time and a high level of postoperative satisfaction,but it requires training in microsurgery.Local flap coverage is simple and suitable for lower level hospitals where staff surgeons may lack microsurgical skills,but it may result in certain minor injuries.

Reconstruction of bone defects of forearm using free vascularized fibular grafts / 中华整形外科杂志

Objective@#To investigate the clinical effect of reconstruction of bone defects of forearm using free vascularized fibular grafts(VFG).@*Methods@#22 patients with bone defects of forearm were treated with free VFG. 6 cases with upper limb bone and soft tissue defects were repaired with free vascularized osteoseptocutaneous fibula as a composite flap. The length of ulna defect ranged from 4 cm to 12 cm and radius defect from 5 cm to 14 cm. The length of harvested fibula ranged from 13 cm to 24 cm. The area of the skin flaps ranged from 12 cm×6 cm to 20 cm×11 cm.@*Results@#All graft bone achieved bone union, with the healing time from 3 to 6 months (mean, 4.5 months). The operation incision healed primarily and all flaps survived with soft texture. All patients were followed up for 12-26 months (mean, 20.5 months). The function of forearm was recovered without refracture. The movement of ankle and the sensation in the leg were normal. According to the Anderson standard at last follow-up visit, the results were excellent in 9 cases, good in 11 cases and fair in 2 cases, with an excellent and good rate of 90.9%.@*Conclusions@#Vascularized fibular grafts VFG is an effective method to repair bone defects of forearm.

Transplantation of flow-through anterolateral thigh flap combined with fibular flap for reconstruction of composite tissue defects at leg / 中华整形外科杂志

Methods@#To explore the transplantation of flow-through anterolateral thigh flap combined with fibular flap for reconstruction of composite tissue defect at leg.@*Method@#12 cases with leg composite tissue defects were reconstructed by flow-through anterolateral thigh flaps combined with fibular flaps. The skin defects ranged from 6 cm×12 cm to 12 cm×20 cm. The bone defects were 4-10 cm in length.The size of flow-through anterolateral thigh flaps was 14 cm×8 cm to 23 cm×13 cm and the fibular osteocutaneous flaps were 6 cm×4 cm to 12 cm×6 cm. The fibular bone was harvested as 7 cm to 13 cm in length.@*Results@#All the flaps survived in 12 cases. Bony reunion was achieved in all the cases. Vascular crisis happened in 2 cases 1 day after operation. Margin necrosis occurred in distal end of one flap, which healed after dressing. All the flaps had soft texture with satisfactory cosmetic and functional result . There was no complication in donor sites.@*Conclusions@#Flow-through anterolateral thigh flap combined with fibular flap can reconstruct soft tissue defect and bone defect simultaneously. It is the ideal method for leg composite tissue defects.

A Survey of Allergic Rhinitis among College Students in Kunming / 昆明医科大学学报

Objective To investigate the distribution,epidemiologic feature and the related risk features of allergic rhinitis among college students in Kunming.Methods Stratified cluster sampling was conducted in each school as a unit.The investigated subjects included 1500 students aged from18 to 29 years old from 7 universities in Kunming,Yunnan Province.The epidemiological investigation was carried out using the designed questionnaire of allergic rhinitis.The results were analyzed.Restlts We had given out 1500 questionnaires and the response rate was 98.9％.The self-reported prevalence of allergic rhinitis was 25.4％ among college students in Kunming,in which,the males' prevalence rate was 29.3％ and the females' was 22.9％.And 3.7％ of the students with allergic rhinitis were combined with asthma and the 19.1％ combined with a history of familial inheritance.The main risk factor was dust.Concltsion The self-reported and prevalence of allergic rhinitis among college students in Kunming is 25.4％.Males' prevalence rate is slightly higher than the females'.The potential risk factors are bronchial asthma and the history of familial inheritance.The mainly inducement is dust,animal fur and plant pollen.

[Effects of YAP-small interfering RNA on the proliferation and apoptosis of human periodontal ligament stem cells].

OBJECTIVE: To investigate the effects of small interfering RNA (siRNA) targeting YAP on the proliferation and apoptosis of human periodontal ligament stem cells (hPDLSCs). METHODS: Synthesized sequences of siRNA were transfected into hPDLSCs by Lipofectamine™ 2000. The expression of YAP was identified by using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Proliferation activity was detected by using cell counting kit-8 (CCK-8). Changes in the cell cycle and apoptosis rate were detected by using flow cytometry. Results were analyzed by using SPSS 19.0, and P < 0.05 was considered statistically significant. RESULTS: Expression of YAP mRNA and protein were significantly downregulated after 48 h of transfection (P < 0.001). No obvious difference was found in the expression levels of YAP protein between 48 and 72 h, thus indicating that siRNA could inhibit the expression of YAP persistently and effectively. Proliferation activity was inhibited, and apoptosis rate was increased. Cell cycle was changed as the proportion of G1and S phases increased (P < 0.01) and G2 phase decreased (P < 0.05). CONCLUSION: Knocking down YAP gene by siRNA could inhibit proliferation activity, induce apoptosis, and change the cell cycle of hPDLSCs. Thus, YAP could regulate the proliferation and apoptosis of hPDLSCs.

Clinical characteristics of bone metastasis from gastric cancer / 中国肿瘤临床

The bone is a common site of metastasis for gastric cancer. High-risk factors of metastatic gastric cancer include young age, poorly differentiated adenocarcinoma, Borrmann type III tumors, depth of invasion at Se and Pm levels, positive lymph nodes, and gastric cancer with concomitant body of stomach cancer. More than half of the transfer pathway belongs to the non-portal system. Cases of gastric cancer with bone metastasis but without liver metastasis accounted for 69%of the total gastric cancer cases, whereas the incidence rate of bone metastasis with lymph node metastasis (≥3 cm away from the primary lesion) was 27%. In addition to the tumor markers human chorionic gonadotropin and carcinoembryonic antigen, radionuclide scan of the bone metastasis provides diagnostic pathways and reliable basis for treatment. Chemoradiation and surgery as symptomatic treatments are alternative therapies for stomach cancer. Bone metastasis confers unfavorable prognosis, and the survival time is often less than six months.

Effects of YAP-small interfering RNA on the proliferation and apoptosis of human periodontal ligament stem cells / 华西口腔医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of small interfering RNA (siRNA) targeting YAP on the proliferation and apoptosis of human periodontal ligament stem cells (hPDLSCs).</p><p><b>METHODS</b>Synthesized sequences of siRNA were transfected into hPDLSCs by Lipofectamine™ 2000. The expression of YAP was identified by using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Proliferation activity was detected by using cell counting kit-8 (CCK-8). Changes in the cell cycle and apoptosis rate were detected by using flow cytometry. Results were analyzed by using SPSS 19.0, and P < 0.05 was considered statistically significant.</p><p><b>RESULTS</b>Expression of YAP mRNA and protein were significantly downregulated after 48 h of transfection (P < 0.001). No obvious difference was found in the expression levels of YAP protein between 48 and 72 h, thus indicating that siRNA could inhibit the expression of YAP persistently and effectively. Proliferation activity was inhibited, and apoptosis rate was increased. Cell cycle was changed as the proportion of G₁and S phases increased (P < 0.01) and G₂ phase decreased (P < 0.05).</p><p><b>CONCLUSION</b>Knocking down YAP gene by siRNA could inhibit proliferation activity, induce apoptosis, and change the cell cycle of hPDLSCs. Thus, YAP could regulate the proliferation and apoptosis of hPDLSCs.</p>