***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background : Bevacizumab and temsirolimus are active agents in gynecologic tumors .  Temsirolimus attenuates upregulation of HIF-1α levels , a resistance mechanism for antiangiogenics , and targets the PI3-kinase/AKT/mTOR axis , commonly aberrant in these tumors Patients and Methods : We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus .  Results : Median age of the 41 women was 60 years ( range , 33 - 80 years ) ; median number of prior systemic therapies was 4 ( 1 - 11 ) .  Grade 3 or 4 treatment-related toxicities included : thrombocytopenia ( 10 % ) , mucositis ( 2 % ) , hypertension ( 2 % ) , hypercholesterolemia ( 2 % ) , fatigue ( 7 % ) , elevated aspartate aminotransferase ( 2 % ) , and neutropenia ( 2 % ) . Twenty-nine patients ( 71 % ) experienced no treatment-related toxicity greater than grade 2 . Full FDA -approved doses of both drugs ( bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25 mg IV weekly ) were administered without dose-limiting toxicity . Eight patients ( 20 % ) achieved stable disease ( SD ) ≥ 6 months and 7 patients ( 17 % ) , a partial response ( PR ) [ total = 15/41 patients ( 37 % ) ] . Eight of 13 patients ( 62 % ) with high- grade serous histology ( ovarian or primary peritoneal ) achieved SD ≥ 6 months/PR . Conclusion : Bevacizumab and temsirolimus was well tolerated . Thirty-seven percent of heavily-pretreated patients achieved SD ≥ 6 months/PR , suggesting that this combination warrants further study Background : Two strategies to interrogate the insulin growth factor 1 receptor ( IGF-1R ) pathway were investigated : vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3 K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation , angiogenesis , and stem cell propagation . Methods : A phase I , multi-cohort dose escalation study was conducted in patients with advanced solid tumours . Patients received dalotuzumab ( 10 mg kg–1 ) and escalating doses of MK-2206 ( 90–200 mg ) or escalating doses of dalotuzumab ( 7.5–10 mg kg–1 ) and MK-0752 ( 1800 mg ) weekly . Upon maximum tolerated dose determination , patients with low-RAS signature , high-IGF1 expression ovarian cancer were r and omised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus , whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752 . Results : A total of 47 patients were enrolled : 29 in part A ( 18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm ) and 18 in part B ( 6 in each arm ) . Dose-limiting toxicities ( DLTs ) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction , maculopapular rash , and gastrointestinal inflammation . For dalotuzumab/MK-0752 , DLTs included grade 3 dehydration , rash , and diarrhoea . Seven patients remained on study for > 4 cycles . Conclusions : Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable . Further developments of prospect ively vali date d predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed Concanavalin A ( Con A ) , a mannose or glucose specific legume lectin , is well known for its anti-proliferative and cytotoxic effect on different types of cancer cells , through its binding to the membrane receptors leading to a major stimulus for the induction of distinct metabolic responses . Recently it has been also been proved that , Con A induces autophagy in hepatoma cells through internalization and mitochondria mediated pathway involving a mitochondrial interacting protein named Bcl2/E1B-19kDa protein-interacting protein 3 ( BNIP3 ) . Through this current endeavor , we propose a membrane associated pathway involved in Con A induced autophagy , taking Human cervical cancer ( HeLa ) cell as a cancer model . Here , we deciphered the role of membrane mediated phosphatidylinositol 3 kinase (PI3K)/Akt/mTOR ( mammalian target of rapamycin ) and MEK/Extracellular signal-regulated kinases ( ERK ) pathway in Con A induced autophagy in HeLa cells . Subsequently , we found that Con A treatment suppresses the PI3K/Akt/mTOR and up regulates the MEK/ERK pathway leading to the activation of autophagy . This study will further help us to underst and the mechanism behind the autophagic pathway induced by Con A and simultaneously it will strengthen its effective use as a prospect i ve cancer chemo-therapeutic Cisplatin‐based chemoradiation ( CRT ) is the st and ard treatment for patients with locally advanced cervical cancer . Epidermal growth factor receptor ( EGFR ) is frequently overexpressed in cervical cancer , and EGFR inhibition itself has antitumor effects and potentiates CRT . Results of a previous phase 1 trial of the EGFR inhibitor erlotinib combined with cisplatin‐based CRT ( E + CRT ) recommended a phase 2 erlotinib dose of 150 mg/day Background : We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose , assess pharmacokinetics ( PK ) , pharmacodynamic activity and pre clinical antitumour efficacy of the combination of sirolimus and gemcitabine . Methods : Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m−2 on days 1 and 8 . Dose escalation depended on dose-limiting toxicity ( DLT ) rate during the first 3-week period . Paired skin biopsies were evaluated for phosphorylated S6 ( pS6 ) as marker of mTOR ( mammalian target of rapamycin ) inhibition . Pharmacokinetics and pre clinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted . Results : Three DLTs were observed : grade 3 transaminitis , grade 3 thrombocytopenia and grade 4 thrombocytopenia . Common treatment-related adverse events included anaemia , neutropenia , thrombocytopenia and transaminitis . Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance . In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus . Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment . Conclusions : Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m−2 . Antitumour activity in pre clinical sarcoma models and mTOR signalling inhibition were observed . A phase II study is currently ongoing BACKGROUND Everolimus ( RAD001 ) is an orally administered inhibitor of the mammalian target of rapamycin ( mTOR ) , a therapeutic target for metastatic renal cell carcinoma . We did a phase III , r and omised , double-blind , placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy . METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib , sorafenib , or both , were r and omly assigned in a two to one ratio to receive everolimus 10 mg once daily ( n=272 )  or placebo  ( n=138 ) , in conjunction with best supportive care . R and omisation was done central ly via an interactive voice response system using a vali date d computer system , and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy , with a permuted block size of six . The primary endpoint was progression-free survival , assessed via a blinded , independent central review . The study was design ed to be terminated after 290 events of progression . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00410124 . FINDINGS All r and omised patients were included in efficacy analyses . The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed ( 101 [ 37 % ] events in the everolimus group , 90 [ 65 % ] in the placebo group ; hazard ratio 0.30 , 95 % CI 0.22 - 0.40 , p<0.0001 ; median progression-free survival 4.0 [ 95 % CI 3.7 - 5.5 ] vs 1.9 [ 1.8 - 1.9 ] months ) . Stomatitis ( 107 [ 40 % ] patients in the everolimus group vs 11 [ 8 % ] in the placebo group ) , rash ( 66 [ 25 % ] vs six [ 4 % ] ) , and fatigue ( 53 [ 20 % ] vs 22 [ 16 % ] ) were the most commonly reported adverse events , but were mostly mild or moderate in severity . Pneumonitis ( any grade ) was detected in 22 ( 8 % ) patients in the everolimus group , of whom eight had pneumonitis of grade 3 severity . INTERPRETATION Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies BACKGROUND We performed a single institution , phase I study of sirolimus and bevacizumab , in order to determine the dose limiting toxicity ( DLT ) and recommended phase II doses . PATIENTS AND METHODS Eligible patients had previously treated advanced malignancies and were enrolled in three cohorts .  Sirolimus 90 mg PO weekly ( 45 mg on days 1 and 2 ) was combined with bevacizumab 7.5mg/kg ( cohort # 1 ) or bevacizumab 15 mg/kg ( cohort # 2 ) IV q3weeks . Sirolimus 4 mg PO daily was combined with bevacizumab 15 mg/kg IV q3weeks ( cohort # 3 ) . RESULTS Twenty-eight patients enrolled . The most common tumour types were colorectal ( 21 % ) , head/neck ( 14 % ) , and renal cell ( 11 % ) . No DLTs were observed in cohorts # 1 ( 4 patients ) and # 2 ( 12 patients ) , while two DLTs ( grade 3 confusion and grade 3 fatigue ) were observed in the first six patients in cohort # 3 ( 12 patients ) . The most common grade 3 toxicities were fatigue ( 18 % ) , hypertension ( 14 % ) and anorexia ( 11 % ) . There were no responses , but one patient has had stable disease for 78 weeks . CONCLUSIONS The combination of sirolimus and bevacizumab at full doses is tolerable in the majority of patients . The availability and cost of sirolimus compared with other mTOR inhibitors make this an attractive agent to combine with bevacizumab This study is to investigate the antitumor activity of  ophiopogonin B ( OP-B ) .  MTT assay  , flow cytometric analysis , acridine orange staining , Lyso-Tracker Red staining and HeLa-GFP-LC3 transfect cells assay were used to detect the proliferation activity , apoptosis and autophagy of HeLa cells . The results showed that OP-B exerted potent antiproliferative activity on HeLa cells , the cell growth inhibition effect of OP-B was not due to apoptosis and OP-B could induce autophagy of HeLa cells . OP-B also induced the protein expression up-regulation of Beclin-1 and promoted LC3 I transformation LC3 II , which were representative proteins of autophagy . Furthermore , 3-MA , an inhibitor of autophagy , not only inhibited OP-B-mediated autophagy but also almost completely reversed the antiproliferative effect of OP-B , suggesting that the growth inhibition effect of OP-B was autophagy dependent . Western blotting demonstrated that OP-B inhibited the phosphorylation of Akt and its ' downstream vital protein , such as mTOR and p70S6 K . In addition , 
    Output:
    
Treatment with mTOR inhibitors in general was well tolerated in patients with metastatic disease .
The predominant toxicities were grade 1 and 2 .
The phase 1 trials included in this review demonstrated that mTOR inhibitor treatments are feasible and safe .