Publications by authors named "P Connor Johnson"

7,037 Publications

The bitter end: T2R bitter receptor agonists elevate nuclear calcium and induce apoptosis in non-ciliated airway epithelial cells.

Cell Calcium 2021 Nov 8;101:102499. Epub 2021 Nov 8.

Department of Otorhinolaryngology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA. Electronic address:

Bitter taste receptors (T2Rs) localize to airway motile cilia and initiate innate immune responses in retaliation to bacterial quorum sensing molecules. Activation of cilia T2Rs leads to calcium-driven NO production that increases cilia beating and directly kills bacteria. Several diseases, including chronic rhinosinusitis, COPD, and cystic fibrosis, are characterized by loss of motile cilia and/or squamous metaplasia. To understand T2R function within the altered landscape of airway disease, we studied T2Rs in non-ciliated airway cell lines and primary cells. Several T2Rs localize to the nucleus in de-differentiated cells that typically localize to cilia in differentiated cells. As cilia and nuclear import utilize shared proteins, some T2Rs may target to the nucleus in the absence of motile cilia. T2R agonists selectively elevated nuclear and mitochondrial calcium through a G-protein-coupled receptor phospholipase C mechanism. Additionally, T2R agonists decreased nuclear cAMP, increased nitric oxide, and increased cGMP, consistent with T2R signaling. Furthermore, exposure to T2R agonists led to nuclear calcium-induced mitochondrial depolarization and caspase activation. T2R agonists induced apoptosis in primary bronchial and nasal cells differentiated at air-liquid interface but then induced to a squamous phenotype by apical submersion. Air-exposed well-differentiated cells did not die. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.
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http://dx.doi.org/10.1016/j.ceca.2021.102499DOI Listing
November 2021

Radiomics Predicts for Distant Metastasis in Locally Advanced Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma.

Cancers (Basel) 2021 Nov 14;13(22). Epub 2021 Nov 14.

Department of Radiation Oncology, University of Miami, Miami, FL 33136, USA.

(1) Background and purpose: clinical trials have unsuccessfully tried to de-escalate treatment in locally advanced human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with the goal of reducing treatment toxicity. The aim of this study was to explore the role of radiomics for risk stratification in this patient population to guide treatment. (2) Methods: the study population consisted of 225 patients with locally advanced HPV+ OPSCC treated with curative-intent radiation or chemoradiation therapy. Appearance of distant metastasis was used as the endpoint event. Radiomics data were extracted from the gross tumor volumes (GTVs) identified on the planning CT, with gray level being discretized using three different bin widths (8, 16, and 32). The data extracted for the groups with and without distant metastasis were subsequently balanced using three different algorithms including synthetic minority over-sampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and borderline SMOTE. From these different combinations, a total of nine radiomics datasets were derived. Top features that minimized redundancy while maximizing relevance to the endpoint were selected individually and collectively for the nine radiomics datasets to build support vector machine (SVM) based predictive classifiers. Performance of the developed classifiers was evaluated by receiver operating characteristic (ROC) curve analysis. (3) Results: of the 225 locally advanced HPV+ OPSCC patients being studied, 9.3% had developed distant metastases at last follow-up. SVM classifiers built for the nine radiomics dataset using either their own respective top features or the top consensus ones were all able to differentiate the two cohorts at a level of excellence or beyond, with ROC area under curve (AUC) ranging from 0.84 to 0.95 (median = 0.90). ROC comparisons further revealed that the majority of the built classifiers did not distinguish the two cohorts significantly better than each other. (4) Conclusions: radiomics demonstrated discriminative ability in distinguishing patients with locally advanced HPV+ OPSCC who went on to develop distant metastasis after completion of definitive chemoradiation or radiation alone and may serve to risk stratify this patient population with the purpose of guiding the appropriate therapy.
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http://dx.doi.org/10.3390/cancers13225689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616361PMC
November 2021

Sex-Dependent Effects of Eicosapentaenoic Acid on Hepatic Steatosis in UCP1 Knockout Mice.

Biomedicines 2021 Oct 27;9(11). Epub 2021 Oct 27.

Department of Nutritional Sciences, Obesity Research Institute, Texas Tech University, Lubbock, TX 79409, USA.

Visceral obesity may be a driving factor in nonalcoholic fatty liver disease (NAFLD) development. Previous studies have shown that the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), ameliorates obesity in high-fat (HF) fed male, C57Bl/6 mice at thermoneutral conditions, independent of uncoupling protein 1 (UCP1). Our goals herein were to investigate sex-dependent mechanisms of EPA in the livers of wild type (WT) and UCP1 knockout (KO) male and female mice fed a HF diet (45% kcal fat; WT-HF, KO-HF) with or without supplementation of 36 g/kg EPA (WT-EPA, KO-EPA). KO significantly increased body weight in males, with no significant reductions with EPA in the WT or KO groups. In females, there were no significant differences in body weight among KO groups and no effects of EPA. In males, liver TGs were significantly higher in the KO-HF group and reduced with EPA, which was not observed in females. Accordingly, gene and protein markers of mitochondrial oxidation, peroxisomal biogenesis and oxidation, as well as metabolic futile cycles were sex-dependently impacted by KO and EPA supplementation. These findings suggest a genotypic difference in response to dietary EPA supplementation on the livers of male and female mice with diet-induced obesity and housed at thermoneutrality.
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http://dx.doi.org/10.3390/biomedicines9111549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615653PMC
October 2021

Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial.

Lancet Haematol 2021 Dec;8(12):e879-e890

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

Background: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration.

Methods: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort.

Findings: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli.

Interpretation: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics.

Funding: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.
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http://dx.doi.org/10.1016/S2352-3026(21)00307-0DOI Listing
December 2021

DSM-5 and ICD-11 alcohol use disorder criteria in young adult regular drinkers: Lifetime prevalence and age of onset.

Drug Alcohol Depend 2021 Nov 17;229(Pt B):109184. Epub 2021 Nov 17.

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Background: Alcohol Use Disorder (AUD) is a significant contributor to global disease burden. AUD has a relatively early onset during young adulthood (Teesson et al., 2010). However, compared to AUD in adults, we have relatively little understanding of AUD in adolescents and emerging adults.

Methods: The RADAR study is a prospective cohort study designed to investigate the emergence of AUD in community-dwelling adolescents and emerging adults across Australia (age range = 18-21 at baseline). At 6 monthly intervals over 2.5 years, participants were interviewed regarding alcohol consumption and alcohol use disorder criteria by clinical psychologists using the SCID-IV-RV. This paper reports the baseline findings of the RADAR cohort.

Results: Proportions of lifetime criteria endorsement among regular drinkers varied considerably. Tolerance was the most endorsed criterion (50.3%), followed by Social Problems (10.4%) and Larger/Longer (9.0%). The median age of onset for most individual AUD criteria was 18 years of age. 18.4% of our cohort met DSM-5 AUD diagnosis in their lifetime to date, and 16.8% met ICD-11 dependence. When removing Tolerance from the AUD criteria, DSM-5 AUD lifetime prevalence reduced to 11.0%, and ICD-11 AUD lifetime prevalence fell to 7.1% in our cohort.

Conclusions: Variable rates of criteria endorsement likely reflect both true differences in the experience of AUD criteria and methodological challenges in the assessment of AUD in an emerging adult age group. High rates of tolerance to the effects of alcohol, and relatively low rates of drinking larger/longer than intended are discussed considering methodological challenges in assessing these criteria in young adults.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.109184DOI Listing
November 2021
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