Biology subjects

Adkins, D.

Publications and source records attributed to Adkins, D..

4 recordsLinked to original sources

bioRxiv2023

Tipifarnib potentiates the antitumor effects of PI3Kα inhibition in PIK3CA- and HRAS-dysregulated HNSCC via convergent inhibition of mTOR activity

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase inhibitor, and alpelisib, a PI3K inhibitor, in multiple molecularly defined subsets of HNSCC. We find that tipifarnib synergizes with alpelisib at the level of mTOR in PI3K-or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. Based on these findings, we have launched the KURRENT-HN trial to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. SignificanceBacked by strong mechanistic rationale, the combination of alpelisib and tipifarnib has the potential to benefit >45% of R/M HNSCC patients. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, thereby enhancing their clinical utility.

cancer biology↗

bioRxiv2021

Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

PurposeTobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental DesignWhole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. ResultsLow expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. ConclusionsIn HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobaccos primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

cancer biology↗

bioRxiv2019

Subthreshold psychosis symptoms associated with molecular genetic risk in a population-based cohort: Findings from Generation Scotland

ImportanceSubthreshold psychosis symptoms in the general population may be associated with genetic risk for schizophrenia. In this analysis, empirically-derived symptom factor scores led to a detection of significant and robust polygenic signal.\n\nObjectiveThis study sought to optimize genetic association with data-driven symptom factor scores, accounting for cohort factor structure and sex differences.\n\nDesignEFA-derived symptom factor scores were regressed onto PRS for schizophrenia in models accounting for age and genetic ancestry principal components. Follow-up examination of symptom factor score associations with other related genetic risks included ADHD, autism, bipolar disorder, major depression, and neuroticism.\n\nParticipantsThis study examined the newly expanded symptom dataset from the Northern European ancestry cohort, Generation Scotland: Scottish Family Health Study (N = 9,105 individuals 18-65 years of age) comprising common variant and subthreshold psychosis symptom data. A total of 5,391 females and 3,713 males with age M[SD] = 45.2 [13] were included in the final analyses.\n\nMain Outcome and MeasureSubthreshold psychosis symptoms were measured using the Schizotypal Personality Questionnaire-Brief (SPQ-B). Primary phenotypic factor scores and genome-wide polygenic risk scores (PRS) reflected weighted sum scores and were examined as continuous measures. Polygenic risk scores were calculated from genome-wide association summary statistics using 7,358,674 imputed common genetic variants passing quality control.\n\nResultsIn males, symptom factor scores were positively associated with polygenic risk for schizophrenia alone and implicated primarily interpersonal/negative symptoms. In females, symptom factor scores were positively associated with polygenic risks for ADHD and autism but not schizophrenia. Scores were robustly associated with genetic risk for neuroticism across both males and females.\n\nConclusions and RelevanceThis study detected a significant association of subthreshold psychosis symptoms with genetic risk for schizophrenia and neuroticism in a population-based sample. Furthermore, important sex differences suggest a need for better understanding of schizophrenia risk assessment in females.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat molecular genetic risks are associated with subthreshold psychosis symptoms in the general population?\n\nFindingsIn a large population-based cohort (N = 9,084), significant associations of polygenic risks with symptoms were observed. Symptoms were associated with genetic risk for schizophrenia in males, for ADHD and autism spectrum disorder in females, and for neuroticism across both males and females.\n\nMeaningAssociations of genetic risk with symptoms in the general population are highly significant and suggest important sex differences.

genetics↗

bioRxiv2018

Bleeding, Cramping, and Satisfaction Among New Copper IUD Users: A Prospective Study

ObjectiveWe assess change in bleeding, cramping, and satisfaction among new copper (Cu) IUD users during the first six months of use, and evaluate the impact of bleeding and cramping on method satisfaction.\n\nMethodsWe recruited 77 women ages 18-45 for this prospective longitudinal observational cohort study. Eligible women reported regular menses, had no exposure to hormonal contraception in the last three months, and desired a Cu IUD for contraception. We collected data prospectively for 180 days following IUD insertion. Monthly, Participants reported bleeding scores using the validated pictorial blood loss assessment chart (PBAC), IUD satisfaction using a five-point Likert scale, and cramping using a seven-level ordinal scale. We used multiple imputation to address nonrandom attrition. Structural equation models for count and ordered outcomes modeled bleeding, cramping, and satisfaction growth curves over the six monthly repeated assessments.\n\nResultsBleeding significantly decreased (approximately 25%) over the course of the study from an estimated PBAC=195 at one month post-insertion to PBAC=151 at six months (t=-2.38, p<0.05). Additionally, IUD satisfaction improved over time (t=2.65, p<0.01), increasing from between \"Neutral\" and \"Satisfied\" to \"Satisfied\", over the six month study. Cramping decreased sharply over the six-month study from between biweekly and weekly, to once or twice a month (t=-4.38, p<0.001). Finally, bleeding, but not cramping, was associated with IUD satisfaction (study mean: t=-2.31, p<0.05; study end: t=-2.81, p<0.01).\n\nConclusionsNew Cu IUD users reported decreasing bleeding and cramping, and increasing IUD satisfaction, over the first six months. Method satisfaction was negatively associated with bleeding.

epidemiology↗