Publications by authors named "Khanh Do"

65 Publications

Safety, anti-tumor activity, and biomarker analysis in a phase 1 trial of the once-daily Wee1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors.

Clin Cancer Res 2021 Apr 16. Epub 2021 Apr 16.

Division of Cancer Treatment and Diagnosis, National Cancer Institute

Purpose: The Wee1 kinase inhibitor adavosertib abrogates cell cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase 2 dose (RPh2D). Here, we report results for once-daily adavosertib.

Patients And Methods: A 3 + 3 dose escalation design was used, with adavosertib given once daily on days 1-5 and 8-12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15-phosphorylated Cdk1/2 [pY15-Cdk]), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers.

Results: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematological; dose-limiting toxicities were grade 4 hematological toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses (PR): 4 ovarian, 2 endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in 4 of 8 patients, suggesting target rebound during the day 5-8 dosing break. One patient who progressed rapidly had a tumor mutation and potentially compensatory overexpression. Baseline overexpression occurred in both of 2 responding patients, only 1 of whom had amplification, and in 0 of 3 non-responding patients.

Conclusions: We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including 2 with baseline mRNA overexpression. Future studies will determine whether overexpression is a predictive biomarker for adavosertib.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0329DOI Listing
April 2021

Immune modulating activity of the CHK1 inhibitor prexasertib and anti-PD-L1 antibody LY3300054 in patients with high-grade serous ovarian cancer and other solid tumors.

Cancer Immunol Immunother 2021 Mar 20. Epub 2021 Mar 20.

Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, USA.

Background: Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation.

Methods: This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform.

Results: Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m prexasertib and 700 mg LY3300054. Dose-limiting toxicities included one episode each of febrile neutropenia (Arm C) and grade 4 neutropenia lasting > 5 days (Arm B). One patient had immune-related AST/ALT elevation after 12 cycles. Three patients with CCNE1-amplified, high-grade serous ovarian cancer (HGSOC) achieved partial response (PR), 2 lasting > 12 months; a fourth such patient maintained stable disease > 12 months. Analysis of peripheral blood demonstrated evidence of CD8 + T-cell activation in response to treatment.

Conclusions: Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples.

Trial Registration: ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018.
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http://dx.doi.org/10.1007/s00262-021-02910-xDOI Listing
March 2021

Phase II Clinical Trial of Everolimus in a Pan-Cancer Cohort of Patients with mTOR Pathway Alterations.

Clin Cancer Res 2021 Mar 16. Epub 2021 Mar 16.

Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Purpose: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored / or mutations.

Experimental Design: Patients with tumors with inactivating / or activating mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations.

Results: Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored (13/30), (15/30), concurrent and (1/30), or (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%-22%]. Median progression-free survival was 2.3 months (95% CI, 1.8-3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5-12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of and high tumor mutation burden, and the other had uterine carcinoma with biallelic -inactivating mutations and PEComa-like pathologic features.

Conclusions: Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4548DOI Listing
March 2021

Global 1-km present and future hourly anthropogenic heat flux.

Sci Data 2021 02 22;8(1):64. Epub 2021 Feb 22.

Department of Transdisciplinary Science and Engineering, Tokyo Institute of Technology, Tokyo, Japan.

Numerical weather prediction models are progressively used to downscale future climate in cities at increasing spatial resolutions. Boundary conditions representing rapidly growing urban areas are imperative to more plausible future predictions. In this work, 1-km global anthropogenic heat emission (AHE) datasets of the present and future are constructed. To improve present AHE maps, 30 arc-second VIIRS satellite imagery outputs such as nighttime lights and night-fires were incorporated along with the LandScan population dataset. A futuristic scenario of AHE was also developed while considering pathways of radiative forcing (i.e. representative concentration pathways), pathways of social conditions (i.e. shared socio-economic pathways), a 1-km future urbanization probability map, and a model to estimate changes in population distribution. The new dataset highlights two distinct features; (1) a more spatially-heterogeneous representation of AHE is captured compared with other recent datasets, and (2) consideration of future urban sprawls and climate change in futuristic AHE maps. Significant increases in projected AHE for multiple cities under a worst-case scenario strengthen the need for further assessment of futuristic AHE.
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http://dx.doi.org/10.1038/s41597-021-00850-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900113PMC
February 2021

Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice.

Front Cell Dev Biol 2021 2;9:632930. Epub 2021 Feb 2.

Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
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http://dx.doi.org/10.3389/fcell.2021.632930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884615PMC
February 2021

Interdisciplinary Assessment of Hygiene Practices in Multiple Locations: Implications for COVID-19 Pandemic Preparedness in Vietnam.

Front Public Health 2020 26;8:589183. Epub 2021 Jan 26.

Department of Psychological Medicine, National University Hospital, Singapore, Singapore.

Due to the shared border with China, Vietnam faced risks from the COVID-19 pandemic at the early stages of the outbreak. Good hygiene practices were considered an effective prevention method, but there were only minimal data on the effectiveness of hygiene practices against the pandemic at the community level. Thus, this study aims to assess hygiene practices in society by using a community-based survey. A cross-sectional study using survey monkey was conducted from December 2019 to February 2020. The Snowball sampling technique was used to recruit participants and exploratory factor analysis was applied to scrutinize the construct validity of the measurement. We used the Tobit regression model to assess the association. Hygiene in a high-risk environment and hygiene in the social and educational environment were two main factors after applying the EFA method. Participants grade community sanitation quite low (around 6 out of 10). Furthermore, the mean score of hygiene practice at a local level in a high-risk environment was slightly low at 6.0. The score of sanitation in the Central region (5.3) was quite low compared to the North (5.8) and the South (6.2). The most high-risk environment was construction, industrial zone and food safety. Moreover, younger respondents were more likely to report poorer hygiene practices in high-risk environments (Coefficient = -1.67; 95% CI = -3.03; -0.32) and social and educational environment (Coefficient = -1.29; 95% CI = -2.54; -0.04). Our study gives an insight into pandemic preparedness at the grassroots level. The findings suggest the necessity of specific communication education for society to improve the compliance of hygiene practices to prevent the spreading of COVID-19.
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http://dx.doi.org/10.3389/fpubh.2020.589183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870988PMC
February 2021

A Phase 1b Study Evaluating the Safety, Tolerability, and Immunogenicity of CMB305, a Lentiviral-Based Prime-Boost Vaccine Regimen, in Patients with Locally Advanced, Relapsed, or Metastatic Cancer Expressing NY-ESO-1.

Oncoimmunology 2020 11 19;9(1):1847846. Epub 2020 Nov 19.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit.
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http://dx.doi.org/10.1080/2162402X.2020.1847846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714520PMC
November 2020

Evaluating Training Need for Epidemic Control in Three Metropolitans: Implications for COVID-19 Preparedness in Vietnam.

Front Public Health 2020 5;8:589331. Epub 2020 Nov 5.

Department of Psychological Medicine, National University Hospital, Singapore, Singapore.

Upon the outbreak of the COVID-19 pandemic, countries worldwide face a critical shortage of human resources in the health sector. Medical students are a potential task force with the capability to support the stretched health sector. This study aims to evaluate their training need for epidemic control in order to employ them effectively. A cross-sectional study was conducted using a web-based survey from December 2019 to February 2020. There were 5,786 observations collected using the snowball sampling technique. Logistic regression was applied to identify factors associated with training participation in epidemic prevention and disaster prevention. Multiple Poisson regression model was constructed to examine factors associated with the number of times they participated in sanitation training and disaster prevention activities in the previous 12 months. Sanitation and health education communication activities had the highest proportion of participants, with 76.5 and 38.4%, followed by examining and treating diseases in the community (13.4%). Those who participated in community activities had a higher number of times to participate in epidemic sanitation training and be involved in disaster prevention. This study informed the need for training programs to prepare medical students for COVID-19 epidemic responses. The training curriculum should include both theoretical approaches and contextual approaches to achieve efficient epidemic control.
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http://dx.doi.org/10.3389/fpubh.2020.589331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674483PMC
November 2020

Phase I trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed solid tumors and lymphomas.

Oncotarget 2020 Nov 3;11(44):3959-3971. Epub 2020 Nov 3.

Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: TRC102 inhibits base excision repair by binding abasic sites and preventing AP endonuclease processing; it potentiates the activity of alkylating agents, including temozolomide, in murine models. In published xenograft studies, TRC102 enhanced the antitumor effect of temozolomide regardless of cell line genetic characteristics, e.g., O6-methylguanine DNA methyltransferase (MGMT), mismatch repair (MMR), or p53 status.

Materials And Methods: We conducted a phase 1 trial of TRC102 with temozolomide given orally on days 1-5 of 28-day cycles in adult patients with refractory solid tumors that had progressed on standard therapy. Tumor induction of nuclear biomarkers of DNA damage response (DDR) γH2AX, pNBs1, and Rad51 was assessed in the context of MGMT and MMR protein expression for expansion cohort patients.

Results: Fifty-two patients were enrolled (37 escalation, 15 expansion) with 51 evaluable for response. The recommended phase 2 dose was 125 mg TRC102, 150 mg/m temozolomide QDx5. Common adverse events (grade 3/4) included anemia (19%), lymphopenia (12%), and neutropenia (10%). Four patients achieved partial responses (1 non-small cell lung cancer, 2 granulosa cell ovarian cancer, and 1 colon cancer) and 13 patients had a best response of stable disease. Retrospective analysis of 15 expansion cohort patients did not demonstrate a correlation between low tumor MGMT expression and patient response, but treatment induced nuclear Rad51 responses in 6 of 12 patients.

Conclusions: The combination of TRC 102 with temozolomide is active, with 4 of 51 patients experiencing a partial response and 13 of 51 experiencing stable disease, and the side effect profile is manageable.
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http://dx.doi.org/10.18632/oncotarget.27784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646836PMC
November 2020

Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2020 Dec 23;86(6):815-827. Epub 2020 Oct 23.

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma.

Methods: This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy.

Results: Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m IV + AT7519 21 mg/m IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli-Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug.

Conclusions: Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue.
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http://dx.doi.org/10.1007/s00280-020-04176-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954579PMC
December 2020

Elovanoid-N32 or RvD6-isomer decrease ACE2 and binding of S protein RBD after injury or INFγ in the eye.

Res Sq 2020 Aug 11. Epub 2020 Aug 11.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes coronavirus disease 2019 (COVID-19) has resulted in a pandemic affecting the most vulnerable in society, triggering a public health crisis and economic tall around the world. Effective treatments to mitigate this virus infection are needed. Since the eye is a route of virus entrance, we use an rat model of corneal inflammation as well as human corneal epithelial cells in culture challenged with IFNγ to study this issue. We explore ways to block the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to angiotensin-converting enzyme 2 (ACE2). Elovanoid (ELV)-N32 or Resolvin D6-isomer (RvD6i), among the lipid mediators studied, consistently decreased the expression of the ACE2 receptor, furin, and integrins in damaged corneas or IFNγ stimulated human corneal epithelial cells (HCEC). There was also a concomitant decrease in the binding of spike RBD with the lipid treatments. Concurrently, we uncovered that the lipid mediators also attenuated the expression of cytokines that participate in the cytokine storm, hyper-inflammation and senescence programming. Thus, the bioactivity of these lipid mediators will contribute to opening therapeutic avenues for COVID-19 by counteracting virus attachment and entrance to the eye and other cells and the ensuing disruptions of homeostasis.
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http://dx.doi.org/10.21203/rs.3.rs-55764/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430585PMC
August 2020

Psychological distress among mountainous farmers in Vietnam: a cross-sectional study of prevalence and associated factors.

BMJ Open 2020 08 6;10(8):e038490. Epub 2020 Aug 6.

Department of Psychological Medicine, National University Hospital, Singapore.

Background: Psychological distress has been known as a major health problem among farmers across the world. In Vietnam, approximately 50% of farmers have lived in rural and mountainous areas. Yet, little has been known about how psychological distress impacts mountainous farmers' health.

Objectives: This study aimed to examine the prevalence and risk factors related to psychological distress among mountainous farmers in Vietnam.

Design And Setting: A cross-sectional study was performed from August to September 2018 in Moc Chau district, Vietnam. A structured questionnaire and face-to-face interviews were used for data collection.

Participants: A random sample of 197 farmers aged at least 18 years, spoke Vietnamese, was not suffering from severe diseases and residing in Moc Chau at the time of the survey were recruited.

Primary And Secondary Outcome Measures: The Kessler Psychological Distress Scale (K6) was employed to measure psychological distress. The tobit and logistic regressions were applied to indicate associated factors.

Results: The prevalence of psychological distress was 38.2% (95% CI 31.3% to 45.5%). Having a greater comorbidities (OR=6.17; 95% CI 1.44 to 26.43), drinking alcohol (OR=3.86; 95% CI 1.02 to 14.59) and obtaining health information from health workers (OR=3.77; 95% CI 1.22 to 11.66) were positively associated with the prevalence of psychological distress. By contrast, being overweight (OR=0.29; 95% CI 0.09 to 0.93), adopting books as the primary source of health information (OR=0.11; 95% CI 0.01 to 0.8), and receiving a higher number of home visits by community health workers (CHWs) (OR=0.38; 95% CI 0.14 to 0.99) were negatively associated with the prevalence of psychological distress.

Conclusion: This study highlighted a high prevalence of psychological distress among mountainous farmers. Providing routine psychological and physical health screening, developing CHWs to provide clinical support and raising health awareness are critical implications for reducing psychological distress in this population.
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http://dx.doi.org/10.1136/bmjopen-2020-038490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412583PMC
August 2020

Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.

Gynecol Oncol 2020 10 25;159(1):150-156. Epub 2020 Jul 25.

Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ, USA. Electronic address:

Objective: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.

Methods: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.

Results: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.

Conclusions: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.

Trial Registration Number: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
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http://dx.doi.org/10.1016/j.ygyno.2020.07.025DOI Listing
October 2020

A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors.

Clin Cancer Res 2020 Nov 21;26(21):5588-5597. Epub 2020 Jul 21.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: DLYE5953A is an antibody-drug conjugate consisting of an anti-LY6E antibody covalently linked to the cytotoxic agent monomethyl auristatin E. This study characterized the safety, pharmacokinetics, immunogenicity, potential biomarkers, and antitumor activity of DLYE5953A in patients with metastatic solid tumors.

Patients And Methods: This was a phase I, open-label, 3+3 dose-escalation, and dose-expansion study of DLYE5953A administered intravenously every 21 days (Q3W) in patients with locally advanced or metastatic solid malignancies.

Results: Sixty-eight patients received DLYE5953A (median, four cycles; range, 1-27). No dose-limiting toxicities were identified during dose escalation (0.2-2.4 mg/kg; = 20). The recommended phase II dose (RP2D) of 2.4 mg/kg Q3W was based on overall safety and tolerability. Dose-expansion cohorts for HER2-negative metastatic breast cancer (HER2-negative MBC; = 23) and non-small cell lung cancer (NSCLC; = 25) patients were enrolled at the RP2D. Among patients receiving DLYE5953A 2.4 mg/kg ( = 55), the most common (≥30%) related adverse events (AEs) included alopecia, fatigue, nausea, and peripheral neuropathy. Grade ≥3 related AEs occurred in 14 of 55 (26%) patients, with neutropenia being the most common (13%). DLYE5953A demonstrated linear total antibody pharmacokinetics at doses of ≥0.8 mg/kg with low unconjugated monomethyl auristatin E levels in blood. Partial response was confirmed in eight of 68 (12%) patients, including three of 29 patients with MBC (10%) and five of 25 patients with NSCLC (20%) at the RP2D. Stable disease was the best response for 37 of 68 (54%) patients.

Conclusions: DLYE5953A administered at 2.4 mg/kg has acceptable safety. Preliminary evidence of antitumor activity in patients with HER2-negative MBC and NSCLC supports further investigation of LY6E as a therapeutic target.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1067DOI Listing
November 2020

Correlation of magnetic and magnetoresistive properties of nanoporous Co/Pd thin multilayers fabricated on anodized TiO templates.

Sci Rep 2020 Jul 2;10(1):10838. Epub 2020 Jul 2.

Department of Physics, University of Gothenburg, 41296, Gothenburg, Sweden.

In this study, we consider a technological approach to obtain a high perpendicular magnetic anisotropy of the Co/Pd multilayers deposited on nanoporous TiO templates of different types of surface morphology. It is found that the use of templates with homogeneous and smoothed surface relief, formed on silicon wafers, ensures conservation of perpendicular anisotropy of the deposited films inherent in the continuous multilayers. Also, their magnetic hardening with doubling of the coercive field is observed. However, inhomogeneous magnetic ordering is revealed in the porous films due to the occurrence of magnetically soft regions near the pore edges and/or inside the pores. Modeling of the field dependences of magnetization and electrical resistance indicates that coherent rotation is the dominant mechanism of magnetization reversal in the porous system instead of the domain-wall motion typical of the continuous multilayers, while their magnetoresistance is determined by electron-magnon scattering, similarly to the continuous counterpart. The preservation of spin waves in the porous films indicates a high uniformity of the magnetic ordering in the fabricated porous systems due to a sufficiently regular pores array introduced into the films, despite the existence of soft-magnetic regions. The results are promising for the design and fabrication of future spintronic devices.
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http://dx.doi.org/10.1038/s41598-020-67677-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331621PMC
July 2020

Coverage of Health Information by Different Sources in Communities: Implication for COVID-19 Epidemic Response.

Int J Environ Res Public Health 2020 05 20;17(10). Epub 2020 May 20.

Department of Psychological Medicine, National University Hospital, Singapore 119074, Singapore.

Health personnel and community workers are at the front line of the COVID-19 emergency response and need to be equipped with adequate knowledge related to epidemics for an effective response. This study aimed to identify the coverage of COVID-19 health information via different sources accessed by health workers and community workers in Vietnam. A cross-sectional study using a web-based survey was carried out from January to February 2020 in Vietnam. Respondent-driven sampling (RDS) was used for recruiting participants. We utilized the exploratory factor analysis (EFA) to examine the construct validity of the questionnaire. A higher percentage of participants knew about "Clinical and pathogen characteristics of COVID-19", compared to "Regulations and policies related to COVID-19". The percentage of participants accessing the information on "Guidelines and policies on prevention and control of COVID-19" was the lowest, especially among medical students. "Mass media and peer-educators" channels had a higher score of accessing COVID-19 information, compared to "Organizations/ agencies/ associations" sources. Participants consumed most of their COVID-19 information via "Internet, online newspapers, social networks". Our findings indicate an urgency to re-design training programs and communication activities for a more effective dissemination of information related to the COVID-19 epidemic or epidemics in general.
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http://dx.doi.org/10.3390/ijerph17103577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277747PMC
May 2020

Complex magnetic ordering in nanoporous [Co/Pd]-IrMn multilayers with perpendicular magnetic anisotropy and its impact on magnetization reversal and magnetoresistance.

Phys Chem Chem Phys 2020 Feb 31;22(6):3661-3674. Epub 2020 Jan 31.

Department of Physics, University of Gothenburg, 41296 Göteborg, Sweden.

We have systematically investigated the magnetization reversal characteristics and magnetoresistance of continuous and nanoporous [Co/Pd]-IrMn multilayered thin films with perpendicular magnetic anisotropy at different temperatures (4-300 K). For their nanostructuring, porosity was induced by means of deposition onto templates of anodized titania with small (∼30 nm in diameter) homogeneously distributed pores. The magnetization reversal and magnetoresistance of the porous films were found to be closely related to the splitting of the ferromagnetic material into regions with different magnetic properties, in correlation with the complex morphology of the porous system. Independent magnetization reversal is detected for these regions, and is accompanied by its strong impact on the magnetic order in the capping IrMn layer. Electron-magnon scattering is found to be a dominant mechanism of magnetoresistance, determining its almost linear field dependence in a high magnetic field and contributing to its magnetoresistance behavior, similar to magnetization reversal, in a low magnetic field. Partial rotation of IrMn magnetic moments, consistent with the magnetization reversal of the ferromagnet, is proposed as an explanation for the two-state resistance behavior observed in switching between high-resistive and low-resistive values at the magnetization reversal of the porous system studied.
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http://dx.doi.org/10.1039/c9cp05947dDOI Listing
February 2020

Membrane-type frizzled-related protein regulates lipidome and transcription for photoreceptor function.

FASEB J 2020 01 28;34(1):912-929. Epub 2019 Nov 28.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA.

Molecular decision-makers of photoreceptor (PRC) membrane organization and gene regulation are critical to understanding sight and retinal degenerations that lead to blindness. Using Mfrp mice, which develop PRC degeneration, we uncovered that membrane-type frizzled-related protein (MFRP) participates in docosahexaenoic acid (DHA, 22:6) enrichment in a manner similar to adiponectin receptor 1 (AdipoR1). Untargeted imaging mass spectrometry demonstrates cell-specific reduction of phospholipids containing 22:6 and very long-chain polyunsaturated fatty acids (VLC-PUFAs) in Adipor1 and Mfrp retinas. Gene expression of pro-inflammatory signaling pathways is increased and gene-encoding proteins for PRC function decrease in both mutants. Thus, we propose that both proteins are necessary for retinal lipidome membrane organization, visual function, and to the understanding of the early pathology of retinal degenerative diseases.
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http://dx.doi.org/10.1096/fj.201902359RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956729PMC
January 2020

Characterizing Unsafe Sexual Behavior among Factory Workers in the Context of Rapid Industrialization in Northern Vietnam.

Int J Environ Res Public Health 2019 12 12;16(24). Epub 2019 Dec 12.

Center of Excellence in Behavioral Medicine, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam.

Industrial workers or factory workers, especially migrant workers, have been found to be vulnerable populations at risk of sexually transmitted infections (STIs). However, there has been a gap in literature regarding health behaviors of migrant factory workers. We conducted a cross-sectional study among 230 factory workers in Hanoi and Bac Ninh cities in Northern Vietnam from July to September 2018 to identify sexual risk practices and related factors among migrant and nonmigrant factory workers. Information collected regarding sexual behavior included the number of sexual partners in the previous 12 months and whether they used condoms in their last sexual intercourse. Two-thirds of participants reported having no sexual activity in the last 12 months, and there was a low percentage of participants using condoms in their last sexual intercourse. Being female, living with spouses/partners, and being a nonimmigrant had a negative association with the lack of using condoms in the last sexual intercourse with casual partners/sex workers, as opposed to having mobility and self-care problems and identifying as a binge drinker. Therefore, workplace-based prevention programs focusing on providing tailored sexual health education and promoting condom use among industrial workers, especially those who are immigrant or migrant workers, in Vietnam should be emphasized.
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http://dx.doi.org/10.3390/ijerph16245085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950032PMC
December 2019

Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors.

Proc Natl Acad Sci U S A 2019 11 11;116(48):24317-24325. Epub 2019 Nov 11.

Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA 70112;

The onset of neurodegenerative diseases activates inflammation that leads to progressive neuronal cell death and impairments in cognition (Alzheimer's disease) and sight (age-related macular degeneration [AMD]). How neuroinflammation can be counteracted is not known. In AMD, amyloid β-peptide (Aβ) accumulates in subretinal drusen. In the 5xFAD retina, we found early functional deficiencies (ERG) without photoreceptor cell (PRC) death and identified early insufficiency in biosynthetic pathways of prohomeostatic/neuroprotective mediators neuroprotectin D1 (NPD1) and elovanoids (ELVs). To mimic an inflammatory milieu in wild-type mouse, we triggered retinal pigment epithelium (RPE) damage/PRC death by subretinally injected oligomeric β-amyloid (OAβ) and observed that ELVs administration counteracted their effects, protecting these cells. In addition, ELVs prevented OAβ-induced changes in gene expression engaged in senescence, inflammation, autophagy, extracellular matrix remodeling, and AMD. Moreover, as OAβ targets the RPE, we used primary human RPE cell cultures and demonstrated that OAβ caused cell damage, while ELVs protected and restored gene expression as in mouse. Our data show OAβ activates senescence as reflected by enhanced expression of p16, MMP1, p53, p21, p27, and Il-6, and of senescence-associated phenotype secretome, followed by RPE and PRC demise, and that ELVs 32 and 34 blunt these events and elicit protection. In addition, ELVs counteracted OAβ-induced expression of genes engaged in AMD, autophagy, and extracellular matrix remodeling. Overall, our data uncovered that ELVs downplay OAβ-senescence program induction and inflammatory transcriptional events and protect RPE cells and PRC, and therefore have potential as a possible therapeutic avenue for AMD.
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http://dx.doi.org/10.1073/pnas.1912959116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883841PMC
November 2019

Knowledge towards Cervical and Breast Cancers among Industrial Workers: Results from a Multisite Study in Northern Vietnam.

Int J Environ Res Public Health 2019 11 5;16(21). Epub 2019 Nov 5.

Center of Excellence in Behavioral Medicine, Nguyen Tat Thanh University, Ho Chi Minh City 700000, Vietnam.

Breast and cervical cancer cases are rising among service and industrial women workers in Vietnam. We conducted a cross-sectional study among 287 workers in three factories in Hanoi and Bac Ninh from July to September 2018 to describe the knowledge of these cancers among industrial workers in Northern Vietnam using a structured questionnaire. Factors associated with knowledge of breast and cervical cancer were identified using generalized linear models (GLM). In our study, approximately one-third of participants believed breast cancer was caused by the lack of breastfeeding, exposure to pollution, and chemicals. Less than 50% knew about sexually transmitted infections that can cause cervical cancer or were aware of a vaccine for cervical cancer. Having one sexual partner within the last year was positively associated with having a higher score of knowledge for both diseases. Receiving a medical checkup within the last 12 months and seeking health information via the internet were related to greater breast cancer knowledge. Targeted education campaigns are needed to ensure proper knowledge and improve awareness of breast cancer and cervical cancer among industrial workers.
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http://dx.doi.org/10.3390/ijerph16214301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862634PMC
November 2019

The CHK1 Inhibitor Prexasertib Exhibits Monotherapy Activity in High-Grade Serous Ovarian Cancer Models and Sensitizes to PARP Inhibition.

Clin Cancer Res 2019 10 13;25(20):6127-6140. Epub 2019 Aug 13.

Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: PARP inhibitors are approved for the treatment of high-grade serous ovarian cancers (HGSOC). Therapeutic resistance, resulting from restoration of homologous recombination (HR) repair or replication fork stabilization, is a pressing clinical problem. We assessed the activity of prexasertib, a checkpoint kinase 1 (CHK1) inhibitor known to cause replication catastrophe, as monotherapy and in combination with the PARP inhibitor olaparib in preclinical models of HGSOC, including those with acquired PARP inhibitor resistance.

Experimental Design: Prexasertib was tested as a single agent or in combination with olaparib in 14 clinically annotated and molecularly characterized luciferized HGSOC patient-derived xenograft (PDX) models and in a panel of ovarian cancer cell lines. The ability of prexasertib to impair HR repair and replication fork stability was also assessed.

Results: Prexasertib monotherapy demonstrated antitumor activity across the 14 PDX models. Thirteen models were resistant to olaparib monotherapy, including 4 carrying mutation. The combination of olaparib with prexasertib was synergistic and produced significant tumor growth inhibition in an olaparib-resistant model and further augmented the degree and durability of response in the olaparib-sensitive model. HGSOC cell lines, including those with acquired PARP inhibitor resistance, were also sensitive to prexasertib, associated with induction of DNA damage and replication stress. Prexasertib also sensitized these cell lines to PARP inhibition and compromised both HR repair and replication fork stability.

Conclusions: Prexasertib exhibits monotherapy activity in PARP inhibitor-resistant HGSOC PDX and cell line models, reverses restored HR and replication fork stability, and synergizes with PARP inhibition.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801076PMC
October 2019

Interplay between spin-crossover and luminescence in a multifunctional single crystal iron(ii) complex: towards a new generation of molecular sensors.

Chem Sci 2019 Jul 14;10(28):6791-6798. Epub 2019 Jun 14.

Groupe d'Etude de la Matière Condensée , CNRS UMR8635 , Université de Versailles Saint Quentin , Université Paris-Saclay , 45 Avenue des Etats-Unis , 78035 Versailles cedex , France . Email:

We present a new example of a mononuclear iron(ii) complex exhibiting a correlated spin-crossover (SCO) transition and strong fluorescence, whose coordination sphere is saturated, for the first time, by six phosphorescent ligands. The interplay between SCO and light emission properties in the thermal region of the spin transition was investigated by means of magnetic, fluorescence, optical absorption and optical microscopy measurements on a single crystal. Overall, the results show an excellent correlation between fluorescence and magnetic data of the present gradual transition, indicating an extreme sensitivity of the optical activity of the ligand to the spin state of the active iron(ii) ions. These results open the way for conceiving new prototypes of pressure and temperature sensors based on this synergy between SCO and luminescence properties. In particular, the fact that cooperative SCO material is not a prerequisite for obtaining such synergetic effects, is useful for the design of thin films or nanoparticles, in which the cooperativity is reduced, for appropriate implementation in nanosized devices to enhance the sensing properties at the nanoscale.
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http://dx.doi.org/10.1039/c9sc02331cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640196PMC
July 2019

Pulsed-laser irradiation of multifunctional gold nanoshells to overcome trastuzumab resistance in HER2-overexpressing breast cancer.

J Exp Clin Cancer Res 2019 Jul 12;38(1):306. Epub 2019 Jul 12.

Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire Pathologie, UMR-S942, F-75010, Paris, France.

Background: HER2-overexpressing metastatic breast cancers are challenging practice in oncology when they become resistant to anti-HER2 therapies such as trastuzumab. In these clinical situations, HER2-overexpression persists in metastatic localizations, and can thus be used for active targeting using innovative therapeutic approaches. Functionalized gold nanoparticles with anti-HER2 antibody can be stimulated by near-infrared light to induce hyperthermia.

Methods: Here, hybrid anti-HER2 gold nanoshells were engineered for photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer xenografts.

Results: When gold nanoshells were administered in HER2-tumor xenografts, no toxicity was observed. A detailed pharmacokinetic study showed a time-dependent accumulation of gold nanoshells within the tumors, significantly greater with functionalized gold nanoshells at 72 h. This enabled us to optimize the treatment protocol and irradiate the mice when the anti-HER2 gold nanoshells had accumulated most in the tumors. After weekly injections of anti-HER2 gold nanoshells, and repeated irradiations with a femtosecond-pulsed laser over four weeks, tumor growth was significantly inhibited. Detailed tissue microscopic analyses showed that the tumor growth inhibition was due to an anti-angiogenic effect, coherent with a preferential distribution of the nanoshells in tumor microvessels. We also showed a direct tumor cell effect with apoptosis and inhibition of proliferation, coherent with an immune-mediated targeting of tumor cells by anti-HER2 nanoshells.

Conclusion: This preclinical study thus supports the use of anti-HER2 gold nanoshells and photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer.
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http://dx.doi.org/10.1186/s13046-019-1305-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626398PMC
July 2019

First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1.

Clin Cancer Res 2019 10 21;25(19):5808-5817. Epub 2019 Jun 21.

Division of Oncology, University of Washington, Seattle, Washington.

Purpose: LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells . LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1-expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors.

Patients And Methods: Adults with previously treated, advanced, NY-ESO-1-positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 10 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 10 vg, 10 vg, 10 vg x 4 doses).

Results: Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma ( = 24), ovarian ( = 8), melanoma ( = 6), and lung cancer ( = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti-NY-ESO-1-specific CD4 and/or CD8 T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti-NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis.

Conclusions: This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1025DOI Listing
October 2019

Customers' Knowledge, Attitude, and Practices towards Food Hygiene and Safety Standards of Handlers in Food Facilities in Hanoi, Vietnam.

Int J Environ Res Public Health 2018 09 25;15(10). Epub 2018 Sep 25.

Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

Efforts to prevent foodborne illnesses in food facilities require sufficient knowledge on hygiene and safety standards from both food processors and customers. However, studies about knowledge, attitude, and practices of customers towards these issues are constrained. This study explored the knowledge, attitude, and practices (KAP) of customers regarding the practices of food facilities as well as potential associated factors. A cross-sectional survey was conducted in Hanoi from September to October 2015. Questions about knowledge, attitude, and practice towards food hygiene and safety were asked, alongside sociodemographic characteristics. Multivariate Tobit regression was used to identify the associated factors with the KAP. Among 1740 customers, the highest mean score of 98.4 (SD = 10.1) was found in knowledge about practices with raw and cooked food, following by knowledge about environmental practices when processing food (mean = 93.1, SD = 17.3), and knowledge about environmental requirements when processing food (mean = 33.3, SD = 33.3). Most of customers considered the processing and selling of hygienic meals without leaving any food overnight as the most important feature for food facilities (73.8%). About 63.2% of participants chose not to report food safety violation by facilities to authorities. The higher score of knowledge was found in groups of people who were not single, had college/university or higher education, and had specific criteria when choosing their places to eat. These findings imply the need for enhancing customers' protection systems, the capability of inspecting and supervising the food processing progress by local authorities, and the awareness of customers about the environmental requirements of food facilities.
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http://dx.doi.org/10.3390/ijerph15102101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211044PMC
September 2018

Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids.

Cancer Discov 2018 11 13;8(11):1404-1421. Epub 2018 Sep 13.

Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic. Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365285PMC
November 2018

A Phase I Study of Ganetespib and Ziv-Aflibercept in Patients with Advanced Carcinomas and Sarcomas.

Oncologist 2018 11 31;23(11):1269-e125. Epub 2018 May 31.

Early Clinical Trials Development Program, Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA

Lessons Learned: The combination of the antiangiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected adverse events and was not tolerable on the dosing schedule tested.Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens.

Background: Although inhibition of angiogenesis is an effective strategy for cancer treatment, acquired resistance to antiangiogenic therapy is common. Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates various oncogenic signaling pathways involved in acquired resistance and has been shown to play a role in angiogenesis. Combining an antiangiogenic agent with an Hsp90 inhibitor has therefore been proposed as a strategy for preventing resistance and improving antitumor activity. We conducted a single-arm phase I study evaluating the combination of ziv-aflibercept, an antiangiogenic drug, with the Hsp90 inhibitor ganetespib.

Methods: Adult patients were eligible if they had recurrent or metastatic gastrointestinal carcinomas, nonsquamous non-small cell lung carcinomas, urothelial carcinomas, or sarcomas that had progressed after at least one line of standard therapy. Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle.

Results: Five patients were treated with the combination. Although three patients achieved stable disease, study treatment was associated with several serious and unexpected adverse events.

Conclusion: The dose escalation phase of this study was not completed, but the limited data obtained suggest that this combination may be too toxic when administered on this dosing schedule.
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http://dx.doi.org/10.1634/theoncologist.2018-0203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291327PMC
November 2018

Evaluating Food Safety Knowledge and Practices of Food Processors and Sellers Working in Food Facilities in Hanoi, Vietnam.

J Food Prot 2018 04;81(4):646-652

2 Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

Consumption of fast food and street food is increasingly common among Vietnamese, particularly in large cities. The high daily demand for these convenient food services, together with a poor management system, has raised concerns about food hygiene and safety (FHS). This study aimed to examine the FHS knowledge and practices of food processors and sellers in food facilities in Hanoi, Vietnam, and to identify their associated factors. A cross-sectional study was conducted with 1,760 food processors and sellers in restaurants, fast food stores, food stalls, and street vendors in Hanoi in 2015. We assessed each participant's FHS knowledge using a self-report questionnaire and their FHS practices using a checklist. Tobit regression was used to determine potential factors associated with FHS knowledge and practices, including demographics, training experience, and frequency of health examination. Overall, we observed a lack of FHS knowledge among respondents across three domains, including standard requirements for food facilities (18%), food processing procedures (29%), and food poisoning prevention (11%). Only 25.9 and 38.1% of participants used caps and masks, respectively, and 12.8% of food processors reported direct hand contact with food. After adjusting for socioeconomic characteristics, these factors significantly predicted increased FHS knowledge and practice scores: (i) working at restaurants and food stalls, (ii) having FHS training, (iii) having had a physical examination, and (iv) having taken a stool test within the last year. These findings highlight the need of continuous training to improve FHS knowledge and practices among food processors and food sellers. Moreover, regular monitoring of food facilities, combined with medical examination of their staff, should be performed to ensure food safety.
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http://dx.doi.org/10.4315/0362-028X.JFP-17-161DOI Listing
April 2018

Factors Associated with Cigarette Smoking and Motivation to Quit among Street Food Sellers in Vietnam.

Int J Environ Res Public Health 2018 01 29;15(2). Epub 2018 Jan 29.

Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.

Since 2013, smoke-free signs in public places, including in restaurants and food stores, have been introduced in Vietnam, aiming to prevent passive smoking. Although extensive research has been carried out on second-hand smoking among clients in public places (e.g., hospitals, restaurants) in Vietnam, no single study exists which captures the current practice of smoking among street food outlets. This study aims to estimate the prevalence of smoking and identify factors associated with smoking status and cessation motivation amongst food sellers in Vietnam. A cross-sectional study involving 1733 food providers at outlets was conducted in 29 districts in Hanoi capital, Vietnam, in 2015. The prevalence of smoking amongst food sellers was determined to be 8.5% (25% for men and 0.8% for women). The enforcement of the smoke-free policy remains modest, since only 7.9% observed outlets complied with the law, providing a room designated for smokers. Although approximately 80% of the participants were aware of the indoor smoke-free regulations in public places, such as restaurants and food stores, 40.2% of smokers reported no intention of quitting smoking. A percentage of 37.6% of current smokers reported that despite having intentions to quit, they did not receive any form of support for smoking cessation. Being male and having hazardous drinking habits and a poor quality of life were all factors that were significantly associated with smoking status. Additionally, having awareness of smoking's adverse effects and being frequently supervised by the authority were associated with a greater motivation to quit. This study highlights the importance of an accompanying education and smoking cessation program in addition to the frequent inspection and reinforcement of smoke-free policy in food stores. This research extends on our knowledge of smoking prevalence and its factors related to smoking events and motivation to quit among street food outlets. Overall, this study strengthens the idea that more government efforts towards preventing passive smoking and smoking cessation education are necessary in restaurants and other street food outlets.
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http://dx.doi.org/10.3390/ijerph15020223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858292PMC
January 2018