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1.
JMIR Res Protoc ; 13: e50032, 2024 04 22.
Article in English | MEDLINE | ID: mdl-38648633

ABSTRACT

BACKGROUND: Asian Americans with metastatic cancer are an understudied population. The Describing Asian American Well-Being and Needs in Cancer (DAWN) Study was designed to understand the supportive care needs of Chinese-, Vietnamese-, and Korean-descent (CVK) patients with metastatic cancer. OBJECTIVE: This study aims to present the DAWN Study protocol involving a primarily qualitative, convergent, mixed methods study from multiple perspectives (patients or survivors, caregivers, and health care professionals). METHODS: CVK Americans diagnosed with solid-tumor metastatic cancer and their caregivers were recruited nationwide through various means (registries, community outreach newsletters, newspapers, radio advertisements, etc). Potentially eligible individuals were screened and consented on the web or through a phone interview. The study survey and interview for patients or survivors and caregivers were provided in English, traditional/simplified Chinese and Cantonese/Mandarin, Vietnamese, and Korean, and examined factors related to facing metastatic cancer, including quality of life, cultural values, coping, and cancer-related symptoms. Community-based organizations assisted in recruiting participants, developing and translating study materials, and connecting the team to individuals for conducting interviews in Asian languages. Health care professionals who have experience working with CVK patients or survivors with metastatic solid cancer were recruited through referrals from the DAWN Study community advisory board and were interviewed to understand unmet supportive care needs. RESULTS: Recruitment began in November 2020; data collection was completed in October 2022. A total of 66 patients or survivors, 13 caregivers, and 15 health care professionals completed all portions of the study. We completed data management in December 2023 and will submit results for patients or survivors and caregivers to publication outlets in 2024. CONCLUSIONS: Future findings related to this protocol will describe and understand the supportive care needs of CVK patients or survivors with metastatic cancer and will help develop culturally appropriate psychosocial interventions that target known predictors of unmet supportive care needs in Chinese, Vietnamese, and Korean Americans with metastatic cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50032.


Subject(s)
Asian , Neoplasm Metastasis , Neoplasms , Adult , Aged , Female , Humans , Male , Middle Aged , Asian/psychology , Caregivers/psychology , China/ethnology , East Asian People , Needs Assessment , Neoplasms/therapy , Neoplasms/psychology , Quality of Life , Southeast Asian People , Surveys and Questionnaires , Vietnam/ethnology , Republic of Korea/ethnology , United States/epidemiology
2.
Int J Behav Med ; 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38472713

ABSTRACT

BACKGROUND: Improving quality of life (QOL) in advanced and metastatic cancer is a priority with increasing survivorship. This systematic review synthesizes psychosocial and behavioral interventions incorporating culture with the goal of examining their benefit for understudied and medically underserved populations with advanced and metastatic cancer. METHOD: Reports were systematically screened for (1) a focus on advanced and metastatic cancer survivors, (2) psychosocial or behavioral intervention intended to improve QOL, (3) evidence of incorporating the culture(s) of understudied/underserved populations, and (4) availability in English. Bias was evaluated using the JBI Critical Appraisal Checklist and the Methodological index for non-randomized studies. Qualitative synthesis and quantitative meta-analyses were completed. RESULTS: Eighty-six reports containing 5981 participants' data were examined. Qualitative synthesis of 23 studies identified four overarching themes relevant for incorporating culture in interventions. Meta-analysis of 19 RCTs and 4 quasi-experimental studies containing considerable heterogeneity indicated greater improvements in QOL (g = 0.84), eudaimonic well-being (g = 0.53), distress (g = -0.49), and anxiety (g = -0.37) for main intervention conditions compared to controls. Meta-analysis of 10 single-arm trials containing minimal to moderate heterogeneity found benefit for anxiety (g = -0.54), physical symptoms (g = -0.39), and depression (g = -0.38). CONCLUSION: Psychosocial and behavioral interventions with cultural incorporation appear beneficial for improving QOL-related outcomes in advanced and metastatic cancer. Studies incorporating culture in psychosocial or behavioral interventions offer noteworthy insight and suggestions for future efforts such as attending to deep cultural structure.

3.
BMC Public Health ; 23(1): 2253, 2023 11 16.
Article in English | MEDLINE | ID: mdl-37974135

ABSTRACT

BACKGROUND: Contact tracing has been essential to reducing spread of COVID-19. Singapore leveraged technology to assist with contact tracing efforts using a Bluetooth-based app and token platform called 'TraceTogether'. METHODS: We reviewed the impact of this system during the country's Delta and Omicron waves (24 August 2021 to 17 February 2022) to identify differences in number of close contacts and time savings between full automation using TraceTogether alone as compared to manual contact tracing supplemented by TraceTogether. Characteristics of digital contact tracing app or token users were reviewed. Thereafter, the number of close contacts identified by manual and digital contact tracing methods, and the number of confirmed COVID-19 cases among contacts were analysed. The difference in time taken for identification of close contacts was also determined. FINDINGS: Adoption rate for TraceTogether was high, with 93.3% of cases having a registered device. There was a 9.8 h (34.9%) reduction in time savings for close contacts to be informed using TraceTogether alone compared to manual contact tracing supplemented by TraceTogether. The proportion of close contacts automatically identified through TraceTogether alone and turned positive was 3.6%. For those identified through manual contact tracing supplemented by TraceTogether, this proportion was 12.5% and 6.2% for those served quarantine orders and health risk warnings respectively. INTERPRETATION: The high adoption rate of 'TraceTogether' suggest that digital solutions remain a promising option to improve contact tracing in future epidemics. This may have been through its concurrent use with vaccine differentiated public health measures and policies which engender public trust. There is future potential for utilising such technology in managing communicable diseases to achieve good public health outcomes.


Subject(s)
COVID-19 , Mobile Applications , Humans , COVID-19/prevention & control , Contact Tracing/methods , Singapore/epidemiology , Quarantine , Public Health
4.
Nature ; 2023 Sep 14.
Article in English | MEDLINE | ID: mdl-37709971
5.
J Osteopath Med ; 121(12): 875-881, 2021 Sep 23.
Article in English | MEDLINE | ID: mdl-34648700

ABSTRACT

The Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and other (LGBTQI+) community continues to experience health inequity and unmet needs. This manuscript examines the application of the Four Tenets of Osteopathic Medicine (FTOM) during a patient's self-disclosure of their sexual orientation and/or gender identity to the provider, also known as coming out. Tenet One discusses the interplay between intersectionality and coming out. Tenet Two elucidates how coming out moves toward a balance of homeostasis and self-healing. Tenet Three examines how structure and function can be understood on a personal level and how society influences coming out. Tenet Four explains the resources available to facilitate the previously forementioned changes. By applying the Four Tenets, the provider may more readily understand what "coming out" means on personal and social levels and what implications they may have on their patients' health.


Subject(s)
Intersectional Framework , Osteopathic Medicine , Disclosure , Female , Gender Identity , Health Inequities , Humans , Male , Sexual Behavior
6.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: mdl-34050022

ABSTRACT

Recent studies suggest that admixture with archaic hominins played an important role in facilitating biological adaptations to new environments. For example, interbreeding with Denisovans facilitated the adaptation to high-altitude environments on the Tibetan Plateau. Specifically, the EPAS1 gene, a transcription factor that regulates the response to hypoxia, exhibits strong signatures of both positive selection and introgression from Denisovans in Tibetan individuals. Interestingly, despite being geographically closer to the Denisova Cave, East Asian populations do not harbor as much Denisovan ancestry as populations from Melanesia. Recently, two studies have suggested two independent waves of Denisovan admixture into East Asians, one of which is shared with South Asians and Oceanians. Here, we leverage data from EPAS1 in 78 Tibetan individuals to interrogate which of these two introgression events introduced the EPAS1 beneficial sequence into the ancestral population of Tibetans, and we use the distribution of introgressed segment lengths at this locus to infer the timing of the introgression and selection event. We find that the introgression event unique to East Asians most likely introduced the beneficial haplotype into the ancestral population of Tibetans around 48,700 (16,000-59,500) y ago, and selection started around 9,000 (2,500-42,000) y ago. Our estimates suggest that one of the most convincing examples of adaptive introgression is in fact selection acting on standing archaic variation.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Evolution, Molecular , Haplotypes , Adaptation, Physiological/genetics , Altitude , Humans , Tibet
7.
Genetics ; 212(3): 855-868, 2019 07.
Article in English | MEDLINE | ID: mdl-31123041

ABSTRACT

Pedigrees provide the genealogical relationships among individuals at a fine resolution and serve an important function in many areas of genetic studies. One such use of pedigree information is in the estimation of the short-term effective population size [Formula: see text], which is of great relevance in fields such as conservation genetics. Despite the usefulness of pedigrees, however, they are often an unknown parameter and must be inferred from genetic data. In this study, we present a Bayesian method to jointly estimate pedigrees and [Formula: see text] from genetic markers using Markov Chain Monte Carlo. Our method supports analysis of a large number of markers and individuals within a single generation with the use of a composite likelihood, which significantly increases computational efficiency. We show, on simulated data, that our method is able to jointly estimate relationships up to first cousins and [Formula: see text] with high accuracy. We also apply the method on a real dataset of house sparrows to reconstruct their previously unreported pedigree.


Subject(s)
Models, Genetic , Pedigree , Population/genetics , Bayes Theorem , Female , Genetics, Population/methods , Humans , Male , Markov Chains
8.
Cancer ; 125(14): 2394-2399, 2019 07 15.
Article in English | MEDLINE | ID: mdl-30933354

ABSTRACT

BACKGROUND: A partial response according to the Response Evaluation Criteria in Solid Tumors includes a wide range of changes in tumor size. This study evaluated whether further specification of tumor reduction based on the depth of response (DpR) would provide a more precise association with outcomes for patients with non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. METHODS: A retrospective analysis was performed for the randomized phase 3 CA031 trial in patients with NSCLC treated with carboplatin in combination with nab-paclitaxel or solvent-based paclitaxel. Quartiles according to the maximum tumor reduction from the baseline were defined (quartile 1 [Q1], >0% to 25%; quartile 2 [Q2], >25% to 50%; quartile 3 [Q3], >50% to 75%; and quartile 4 [Q4], >75%) and were compared with those patients with no tumor reduction (NTR). The primary objective was to evaluate the association between DpR and overall survival (OS). RESULTS: Of the 1052 patients enrolled in the CA031 trial, 959 (91%) were evaluable, and they included 365 (38.1%) who were classified as Q1, 327 (34.1%) who were classified as Q2, 131 (13.7%) who were classified as Q3, and 34 (3.5%) who were classified as Q4; 102 had NTR (10.6%). The median OS values for patients in the NTR, Q1, Q2, Q3, and Q4 groups were 4.8, 10.4, 14.5, 19.3, and 23.5 months, respectively. The maximum DpR on treatment was an independent predictor of improved OS in comparison with patients with NTR; the hazard ratio decreased from 0.43 in Q1 to 0.16 in Q4. CONCLUSIONS: DpR was strongly associated with OS in patients with NSCLC receiving first-line platinum-based therapy. Additional studies may help to define the role of DpR in solid tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/mortality , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Response Evaluation Criteria in Solid Tumors , Adult , Aged , Aged, 80 and over , Albumins/therapeutic use , Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Female , Humans , Male , Middle Aged , Organoplatinum Compounds/therapeutic use , Paclitaxel/therapeutic use , Progression-Free Survival , Retrospective Studies , Tumor Burden/drug effects , Young Adult
9.
Drug Des Devel Ther ; 12: 1445-1451, 2018.
Article in English | MEDLINE | ID: mdl-29872267

ABSTRACT

BACKGROUND: Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. CONCLUSION: nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup.


Subject(s)
Albumins/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/therapeutic use , Aged , Aged, 80 and over , Albumins/administration & dosage , Albumins/chemistry , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/chemistry , Carboplatin/administration & dosage , Carboplatin/chemistry , Drug Tolerance , Female , Humans , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Retrospective Studies
10.
Clin Breast Cancer ; 18(5): e919-e926, 2018 10.
Article in English | MEDLINE | ID: mdl-29703690

ABSTRACT

BACKGROUND: In this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. PATIENTS AND METHODS: Quality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. RESULTS: In the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], -0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). CONCLUSION: In its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.


Subject(s)
Albumins/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Paclitaxel/therapeutic use , Albumins/adverse effects , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clinical Trials, Phase III as Topic , Female , Humans , Middle Aged , Neoplasm Metastasis , Paclitaxel/adverse effects , Quality of Life , Survival Analysis
11.
Blood ; 131(7): 782-786, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29288169

ABSTRACT

Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms. Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells; binding alone is insufficient for cytokine independent growth. We further show that the threshold of positive charge in the mutant CALR C terminus influences both binding of mutant CALR to MPL and activation of MPL signaling. We find that mutant CALR binds to the extracellular domain of MPL and that 3 tyrosine residues within the intracellular domain of MPL are required to activate signaling. With respect to mutant CALR function, we show that its lectin-dependent function is required for binding to MPL and for cytokine independent growth, whereas its chaperone and polypeptide-binding functionalities are dispensable. Together, our findings provide additional insights into the mechanism of the pathogenic mutant CALR-MPL interaction in myeloproliferative neoplasms.


Subject(s)
Calreticulin/genetics , Calreticulin/metabolism , Myeloproliferative Disorders/genetics , Protein Interaction Domains and Motifs , Receptors, Thrombopoietin/genetics , Receptors, Thrombopoietin/metabolism , Calreticulin/chemistry , Cells, Cultured , HEK293 Cells , Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , Hematologic Neoplasms/pathology , Humans , Mutagenesis , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Protein Binding , Protein Interaction Domains and Motifs/genetics , Protein Interaction Maps , Receptors, Thrombopoietin/chemistry , Signal Transduction
12.
Lung Cancer (Auckl) ; 8: 207-216, 2017.
Article in English | MEDLINE | ID: mdl-29138610

ABSTRACT

BACKGROUND: Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. METHODS: Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). RESULTS: Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. CONCLUSION: In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.

13.
Science ; 358(6363): 659-662, 2017 11 03.
Article in English | MEDLINE | ID: mdl-28982795

ABSTRACT

Present-day hunter-gatherers (HGs) live in multilevel social groups essential to sustain a population structure characterized by limited levels of within-band relatedness and inbreeding. When these wider social networks evolved among HGs is unknown. To investigate whether the contemporary HG strategy was already present in the Upper Paleolithic, we used complete genome sequences from Sunghir, a site dated to ~34,000 years before the present, containing multiple anatomically modern human individuals. We show that individuals at Sunghir derive from a population of small effective size, with limited kinship and levels of inbreeding similar to HG populations. Our findings suggest that Upper Paleolithic social organization was similar to that of living HGs, with limited relatedness within residential groups embedded in a larger mating network.


Subject(s)
Genome, Human , Reproductive Behavior/history , Social Behavior/history , DNA, Ancient , History, Ancient , Humans , Population Density , Russia
14.
PLoS Genet ; 13(8): e1006963, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28827797

ABSTRACT

Pedigrees contain information about the genealogical relationships among individuals and are of fundamental importance in many areas of genetic studies. However, pedigrees are often unknown and must be inferred from genetic data. Despite the importance of pedigree inference, existing methods are limited to inferring only close relationships or analyzing a small number of individuals or loci. We present a simulated annealing method for estimating pedigrees in large samples of otherwise seemingly unrelated individuals using genome-wide SNP data. The method supports complex pedigree structures such as polygamous families, multi-generational families, and pedigrees in which many of the member individuals are missing. Computational speed is greatly enhanced by the use of a composite likelihood function which approximates the full likelihood. We validate our method on simulated data and show that it can infer distant relatives more accurately than existing methods. Furthermore, we illustrate the utility of the method on a sample of Greenlandic Inuit.


Subject(s)
Data Interpretation, Statistical , Genotype , Models, Genetic , Pedigree , Computer Simulation , Genome, Human/genetics , Haplotypes/genetics , Humans , Likelihood Functions , Polymorphism, Single Nucleotide/genetics
15.
Sci Rep ; 7(1): 268, 2017 03 21.
Article in English | MEDLINE | ID: mdl-28325918

ABSTRACT

Constraint-based optimization, such as flux balance analysis (FBA), has become a standard systems-biology computational method to study cellular metabolisms that are assumed to be in a steady state of optimal growth. The methods are based on optimization while assuming (i) equilibrium of a linear system of ordinary differential equations, and (ii) deterministic data. However, the steady-state assumption is biologically imperfect, and several key stoichiometric coefficients are experimentally inferred from situations of inherent variation. We propose an approach that explicitly acknowledges heterogeneity and conducts a robust analysis of metabolic pathways (RAMP). The basic assumption of steady state is relaxed, and we model the innate heterogeneity of cells probabilistically. Our mathematical study of the stochastic problem shows that FBA is a limiting case of our RAMP method. Moreover, RAMP has the properties that: A) metabolic states are (Lipschitz) continuous with regards to the probabilistic modeling parameters, B) convergent metabolic states are solutions to the deterministic FBA paradigm as the stochastic elements dissipate, and C) RAMP can identify biologically tolerable diversity of a metabolic network in an optimized culture. We benchmark RAMP against traditional FBA on genome-scale metabolic reconstructed models of E. coli, calculating essential genes and comparing with experimental flux data.


Subject(s)
Escherichia coli/genetics , Escherichia coli/metabolism , Metabolic Flux Analysis , Metabolic Networks and Pathways , Systems Biology/methods , Models, Theoretical
16.
Mol Biol Evol ; 34(3): 509-524, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28007980

ABSTRACT

A recent study conducted the first genome-wide scan for selection in Inuit from Greenland using single nucleotide polymorphism chip data. Here, we report that selection in the region with the second most extreme signal of positive selection in Greenlandic Inuit favored a deeply divergent haplotype that is closely related to the sequence in the Denisovan genome, and was likely introgressed from an archaic population. The region contains two genes, WARS2 and TBX15, and has previously been associated with adipose tissue differentiation and body-fat distribution in humans. We show that the adaptively introgressed allele has been under selection in a much larger geographic region than just Greenland. Furthermore, it is associated with changes in expression of WARS2 and TBX15 in multiple tissues including the adrenal gland and subcutaneous adipose tissue, and with regional DNA methylation changes in TBX15.


Subject(s)
Adaptation, Biological/genetics , Inuit/genetics , T-Box Domain Proteins/genetics , Adipose Tissue/physiology , Alleles , Animals , DNA Methylation , DNA, Ancient , Greenland , Haplotypes , Humans , Models, Genetic , Neanderthals , Polymorphism, Single Nucleotide , Selection, Genetic , Sequence Analysis, DNA/methods
17.
Clin Lung Cancer ; 17(5): 367-374, 2016 09.
Article in English | MEDLINE | ID: mdl-27230605

ABSTRACT

PURPOSE: To examine outcomes in a phase 3 trial of nab-paclitaxel plus carboplatin (nab-P/C) versus solvent-based paclitaxel plus carboplatin (sb-P/C) in a subset of patients with advanced non-small-cell lung cancer (NSCLC) and diabetes. PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC received nab-P 100 mg/m2 on days 1, 8, and 15 or sb-P 200 mg/m2 on day 1, both with C at an area under the curve of 6 mg·min/mL on day 1 every 3 weeks. Overall response rate (ORR) and progression-free survival (PFS) were determined by blinded, independent, centralized review. P values were based on chi-square test for ORR and log-rank test for overall survival (OS) and PFS. RESULTS: Of the 1052 randomized patients in the phase 3 trial, 61 had diabetes according to prespecified terms (nab-P/C, 31; sb-P/C, 30). ORR for nab-P/C versus sb-P/C in this subset was 52% versus 27% (relative risk ratio, 1.935; P = .046), median PFS was 10.9 versus 4.9 months (hazard ratio, 0.420; P = .016), and median OS was 17.5 versus 11.1 months (hazard ratio, 0.550; P = .057). Treatment differences in PFS remained significant (P ≤ .036) after adjusting for histology, region, stage, race, and age and also remained significant in OS for histology (P = .039). Patients with diabetes experienced lower rates of grade 3 or higher neutropenia and peripheral neuropathy and higher rates of thrombocytopenia and anemia with nab-P/C versus sb-P/C. CONCLUSION: nab-P/C demonstrated improved efficacy and manageable tolerability in patients with advanced NSCLC and diabetes.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Diabetes Mellitus/physiopathology , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Albumins/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Survival Rate , Treatment Outcome , Young Adult
18.
Cancer Discov ; 6(4): 368-81, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26951227

ABSTRACT

UNLABELLED: Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN. SIGNIFICANCE: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL.


Subject(s)
Calreticulin/genetics , Cell Transformation, Neoplastic/genetics , Mutation , Protein Interaction Domains and Motifs/genetics , Receptors, Thrombopoietin/genetics , Animals , Base Sequence , Bone Marrow Transplantation , Calreticulin/chemistry , Calreticulin/metabolism , Cell Line , Cell Transformation, Neoplastic/metabolism , Disease Models, Animal , Female , Frameshift Mutation , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Mice , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/pathology , Phenotype , Protein Binding , Protein Kinase Inhibitors/pharmacology , Receptors, Thrombopoietin/metabolism , STAT Transcription Factors/metabolism , Signal Transduction , Structure Collapse
20.
Trials ; 16: 575, 2015 Dec 16.
Article in English | MEDLINE | ID: mdl-26673577

ABSTRACT

BACKGROUND: Triple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-paclitaxel-based regimens (with gemcitabine or carboplatin±bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer. TRIAL DESIGN: In this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer. METHODS: In the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment-naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: ≤1 versus>1 year) to nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 plus carboplatin area under the curve 2 mg×min/mL, or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 mg×min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the "winner" of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: ≤1 versus >1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently-assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1. DISCUSSION: The tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01881230 . Date of registration: 17 June 2013.


Subject(s)
Albumins/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Paclitaxel/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Albumins/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/adverse effects , Clinical Protocols , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Neoplasm Metastasis , Paclitaxel/adverse effects , Research Design , Survival Analysis , Time Factors , Treatment Outcome , Triple Negative Breast Neoplasms/mortality , Triple Negative Breast Neoplasms/pathology , Gemcitabine
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