scholarly journals PDCT-12. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi186-vi186
Author(s):  
Abed Rahman Kawakibi ◽  
Sharon Gardner ◽  
Andrew Chi ◽  
Sylvia Kurz ◽  
Patrick Wen ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Clinical Analysis ◽  
Best Response ◽  
Duration Of Response ◽  
Post Radiation ◽  
Cutoff Date ◽  
Tumor Dna

Abstract ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15–73 years old) and post-radiation non-recurrent patients (n=11; 5–19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6–37.9) for recurrent patients and 10.6 months (range: 4.3–20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2–3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1–32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma.

scholarly journals HGG-18. CLINICAL EFFICACY OF ONC201 IN THALAMIC H3 K27M-MUTANT GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii347-iii347
Author(s):  
Abed Rahman Kawakibi ◽  
Rohinton S Tarapore ◽  
Sharon Gardner ◽  
Andrew Chi ◽  
Sylvia Kurz ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Single Agent ◽  
Clinical Analysis ◽  
Best Response ◽  
Duration Of Response ◽  
Post Radiation ◽  
Tumor Dna

Abstract ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3617-3617
Author(s):  
Abed Rahman Kawakibi ◽  
Rohinton Tarapore ◽  
Sharon L. Gardner ◽  
Sylvia Christine Kurz ◽  
Patrick Y. Wen ◽  
...  
Keyword(s):  
Clinical Efficacy ◽  
Single Agent ◽  
Line Radiation ◽  
Primary Tumors ◽  
Best Response ◽  
Duration Of Response ◽  
Post Radiation ◽  
The Brain ◽  
Clinical Trial Information

3617 Background: Diffuse midline gliomas, H3 K27M-mutant are associated with a poor prognosis compared to H3 wild-type gliomas and have no effective therapy following first-line radiation. ONC201 is a bitopic DRD2 antagonist and allosteric ClpP agonist that has shown encouraging single agent efficacy in recurrent H3 K27M-mutant gliomas located in various midline structures of the brain. In addition to tumor and immune cells, the pharmacodynamics of ONC201 extend to stromal cells that can mediate a bystander antitumor response in preclinical models. Given this observation and that the thalamus has the highest extrastriatal expression of DRD2, we report the clinical experience of ONC201 in a subgroup of H3 K27M-mutant glioma patients with primary tumors located in the thalamus. Methods: We analyzed 29 thalamic H3 K27M-mutant glioma patients treated with ONC201 in clinical trials enrolled as of 5/22/19. Nineteen enrolled with recurrent disease whereas 10 enrolled following radiation prior to recurrence. Twelve patients enrolled on NCT03295396, 10 NCT03416530, 4 NCT02525692, and 3 expanded access. Median age was 22 years old (range: 5-70) and baseline KPS was 80 (range: 60-90). Median time from radiation to start of ONC201 was 1.8 months (range: 0.2-8.7) for non-recurrent patients and 7.2 months (range: 1.4-102.0) for recurrent patients. Results: As of 12/18/2019, PFS6 and OS12 measured relative to initiation of ONC201 are 26.3% and 36.8%, respectively, in the recurrent group. For patients initiating ONC201 post-radiation prior to recurrence, median PFS or OS have not been reached with a median follow up of 21.9 months (8.6-26.6) from diagnosis, which surpass historical OS of 13.5 months. Best response for evaluable recurrent patients by RANO: 1 CR, 3 PR, 4 SD, 8 PD, 3 not reported; for non-recurrent patients: 2 PR, 4 SD, 1 PD, 3 not reported. Median duration of response for recurrent patients is 14.0 months (2.0-33.1). ONC201 was well tolerated and no dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. Conclusions: In summary, single agent ONC201 administered at recurrence or following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients. Investigations are ongoing to assess whether micro-environmental DRD2 expression correlates with responses of thalamic H3 K27M-mutant glioma to ONC201. Clinical trial information: NCT03295396, NCT03416530, NCT02525692 .

scholarly journals TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Sha Zhou ◽  
Jianhong Peng ◽  
Liuniu Xiao ◽  
Caixia Zhou ◽  
Yujing Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Free Survival ◽  
Free Survival ◽  
Epigenetic Regulator ◽  
Crc Management ◽  
Disease Free ◽  
Resistance To Chemotherapy

AbstractResistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.

scholarly journals Differential Normalization of Mucosal Interleukin-8 and Interleukin-6 Activity after Helicobacter pyloriEradication

1998 ◽  
Vol 66 (10) ◽  
pp. 4742-4747 ◽  
Author(s):  
Takafumi Ando ◽  
Kazuo Kusugami ◽  
Masahiro Ohsuga ◽  
Kenji Ina ◽  
Masataka Shinoda ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Eradication Therapy ◽  
Interleukin 8 ◽  
Biopsy Specimens ◽  
Mucosal Tissues ◽  
H Pylori ◽  
Triple Treatment

ABSTRACT There is differential resolution of mucosal infiltration with neutrophils and mononuclear cells following successfulHelicobacter pylori eradication. We investigated the effects of H. pylori eradication on mucosal interleukin-8 (IL-8) and IL-6 activity in relation to the resolution of H. pylori-associated gastritis. Eighty-one duodenal ulcer patients with H. pyloriinfection received dual- or triple-treatment eradication therapy, and mucosal biopsy specimens obtained at the initial and follow-up endoscopic examinations were cultured in vitro for 24 h. The levels of IL-8 and IL-6 were measured by enzyme-linked immunosorbent assays. In the 42 patients in whomH. pylori eradication failed, there was little change in the numbers of neutrophils and mononuclear cells infiltrating the mucosa and in IL-8 and IL-6 activity. In the 39 patients in whom H. pylori was eradicated, there was normalization both in the numbers of infiltrating neutrophils and in mucosal IL-8 activity, which was evident within 1 month following therapy. In contrast, there was a gradual resolution of mononuclear cell infiltration over a 6-month period, accompanied by a gradual normalization in IL-6 levels. Addition of H. pylori to cultures of mucosal tissues induced a significant increase in IL-8 activity in both uninfected control subjects and patients from whom H. pylori was eradicated. However, this introduction yielded a significant increase in IL-6 activity only in the latter group. This study indicates a dichotomy in the changes of mucosal IL-8 and IL-6 activity afterH. pylori eradication. The rapid normalization of IL-8 after H. pylori eradication and the ability of H. pylori cells to stimulate IL-8 in control tissues indicate that IL-8 induction is a part of the innate (nonimmune) responses to this organism. In contrast, the results of experiments analyzing IL-6 activity in cultured mucosal tissues suggest that the gradual resolution of mucosal IL-6 activity and mononuclear infiltration after successful eradication observed in vivo may reflect gradually diminishing residual immune responses against H. pylori.

scholarly journals In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas

2013 ◽  
Vol 20 (3) ◽  
pp. 349-359 ◽  
Author(s):  
Rodrigo A Toledo ◽  
Yuejuan Qin ◽  
Subramanya Srikantan ◽  
Nicole Paes Morales ◽  
Qun Li ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Target Genes ◽  
Germline Mutations ◽  
Vascular Tumors ◽  
Wild Type ◽  
Pheochromocytoma Pc12 ◽  
Hereditary Tumors ◽  
Tumor Dna

Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.

Antimalaria Activity of Cassia spectabilis DC Leaf and Its Inhibition Effect in Heme Detoxification

2020 ◽  
Author(s):  
Wiwied - Ekasari ◽  
Dewi Resty Basuki ◽  
Heny - Arwati ◽  
Tutik Sri Wahy
Keyword(s):  
Antimalarial Activity ◽  
Ethanol Extract ◽  
Ic50 Value ◽  
Cassia Spectabilis ◽  
In Vivo Testing ◽  
Chloroquine Diphosphate ◽  
Better Than

Abstract Background In previous studies, Cassia spectabilis DC leaf has shown a good antimalarial activity. Therefore, this study is a follow-up study of leaf activity and mechanism of C. spectabilis DC as an antimalarial. Methods In vitro antimalarial activity testing using P. falciparum which was done with bioassay guide isolation in order to obtain the active compound. In vivo testing towards infected P. berghei mice was conducted to determine the effects of antimalarial prophylaxis and antimalarial activity in combination with artesunate. Whereas, heme detoxification inhibition testing as one of the antimalarial mechanisms was carried out using the Basilico method. Results The results showed that active antimalarial isolate obtained from C. spectabilis DC leaf had a structural pattern that was identical to (-)-7-hydroxyspectaline. Prophylactic test on infected P. berghei mice obtained the highest dose of inhibition percentage of 90% ethanol extract of C. spectabilis DC leaf was 68.61% while positive (doxycycline) control at 100 mg kg-1 was 73.54%. In antimalarial testing in combination with artesunate, it was found that administering 150 mg kg-1 (three times a day) of C. spectabilis DC (D0 − D2) + artesunate (D2) was better than the standard combination of amodiaquine + artesunate with 99.18% and 92.88% inhibition percentage. For the inhibitory activity of heme detoxification from ethanol extract 90%, C. spectabilis DC leaf had IC50 value of 0.375 mg mL-1 which was better than chloroquine diphosphate. Conclusion These results showed that C. spectabilis DC leaves possesses potent antimalarial activity and may offer a potential agent for effective and affordable antimalarial phytomedicine.

scholarly journals Model-Based Roentgen Stereophotogrammetric Analysis to Monitor the Head–Taper Junction in Total Hip Arthroplasty in Vivo—And They Do Move

Materials ◽  
2020 ◽  
Vol 13 (7) ◽  
pp. 1543 ◽  
Author(s):  
Jing Xu ◽  
Robert Sonntag ◽  
J. Philippe Kretzer ◽  
Dominic Taylor ◽  
Raimund Forst ◽  
...  
Keyword(s):  
Femoral Stem ◽  
Geometrical Shape ◽  
Roentgen Stereophotogrammetric Analysis ◽  
Model Based ◽  
Similar Range ◽  
Standard Marker ◽  
Relative Migration

Model-based Roentgen stereophotogrammetric analysis (RSA) using elementary geometrical shape (EGS) models allows migration measurement of implants without the necessity of additional attached implant markers. The aims of this study were: (i) to assess the possibility of measuring potential head–taper movement in THA in vivo using model-based RSA and (ii) to prove the validity of measured head–taper migration data in vitro and in vivo. From a previous RSA study with a 10 years follow-up, retrospectively for n = 45 patients head–taper migration was calculated as the relative migration between femoral ball head and taper of the femoral stem using model-based RSA. A head–taper migration of 0.026 mm/year can be detected with available RSA technology. In vitro validation showed a total migration of 268 ± 11 µm along the taper axis in a similar range to what has been reported using the RSA method. In vivo, a proof for interchangeable applicability of model-based RSA (EGS) and standard marker-based RSA methods was indicated by a significant deviation within the migration result after 12-month follow-up for all translation measurements, which was significantly correlated to the measured head–taper migration (r from 0.40 to 0.67; p < 0.05). The results identified that model-based RSA (EGS) could be used to detect head–taper migration in vivo and the measured movement could be validated in vitro and in vivo as well. Those findings supported the possibility of applying RSA for helping evaluate the head–taper corrosion related failure (trunnionosis).

scholarly journals Association Between Periodontal Disease and Atherosclerotic Cardiovascular Diseases: Revisited

2021 ◽  
Vol 7 ◽  
Author(s):  
Faraedon Zardawi ◽  
Sarhang Gul ◽  
Ali Abdulkareem ◽  
Aram Sha ◽  
Julian Yates
Keyword(s):  
Cardiovascular Disease ◽  
Periodontal Disease ◽  
Atherosclerotic Cardiovascular Disease ◽  
Periodontal Pathogens ◽  
Systemic Level ◽  
Prevalent Disease ◽  
Atherosclerotic Cardiovascular Diseases

Atherosclerotic cardiovascular disease (ACVD) is an inflammatory disease of the coronary arteries associated with atheroma formation, which can cause disability and often death. Periodontitis is ranked as the sixth most prevalent disease affecting humans affecting 740 million people worldwide. In the last few decades, researchers have focused on the effect of periodontal disease (PD) on cardiovascular disease. The aim of this review was to investigate the association between these two diseases. PD is a potential risk factor that may initiate the development, maturation, and instability of atheroma in the arteries. Two mechanisms were proposed to explain such association, either periodontal pathogens directly invade bloodstream or indirectly by increasing systemic level of inflammatory mediators. Interestingly, it has been suggested that improvement in the condition of one disease positively impact the condition of the other one. Highlighting the association between these two diseases, the importance of early diagnosis and treatment of PD and its impact on cardiovascular status may be of great value in reducing the complications associated with ACVDs. Further in vitro and in vivo studies with longer follow up are necessary to confirm the causal relationship between PD and ACVDs.

scholarly journals Evaluation of trained immunity by β‐1, 3 ( d )‐glucan on murine monocytes in vitro and duration of response in vivo

2017 ◽  
Vol 95 (7) ◽  
pp. 601-610 ◽  
Author(s):  
Pablo Garcia‐Valtanen ◽  
Ruth Marian Guzman‐Genuino ◽  
David L Williams ◽  
John D Hayball ◽  
Kerrilyn R Diener
Keyword(s):  
Trained Immunity ◽  
Duration Of Response

scholarly journals Zanamivir Susceptibility Monitoring and Characterization of Influenza Virus Clinical Isolates Obtained during Phase II Clinical Efficacy Studies

2000 ◽  
Vol 44 (1) ◽  
pp. 78-87 ◽  
Author(s):  
J. M. Barnett ◽  
A. Cadman ◽  
D. Gor ◽  
M. Dempsey ◽  
M. Walters ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Efficacy ◽  
Influenza A ◽  
Mdck Cells ◽  
Virus Infections ◽  
Virus Shedding ◽  
Efficacy Trials ◽  
Natural Variants

ABSTRACT Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log1050% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection.

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