tbuckley/cabot-search huggingface dataset:
Advances and controversies in studying sunscreen delivery and toxicity
Authors: Miko Yamada, Yousuf Mohammed, Tarl W Prow
Journal: Advanced Drug Delivery Reviews (2020)

This review critically evaluates the sunscreen delivery and toxicity field. We chose to focus on approved sunscreens in this review. Optimal sunscreen use prevents skin cancer and photoageing but there is an important knowledge gap in sunscreen/skin interactions. Sunscreen delivery is a key for efficacy, but studying sunscreen delivery is not straightforward. We review the strengths and weaknesses of in vitro, excised skin and clinical approaches. Understanding positive and negative sunscreen effects on skin homeostasis is also challenging. The results in this field, especially in vitro testing, are controversial and experimental design varies widely which further supports disparities between some findings. We hypothesize that bias towards showing sunscreen toxicity to increase impact could be problematic. We explore that perception through a detailed review of experimental design, especially in cell culture models. Our conclusion is that emerging, non- and minimally invasive technologies are enabling new approaches to volunteer studies that could significantly improve knowledge of sunscreen delivery and interactions. • Sunscreen use prevents skin cancer, especially in immunocompromised patients. • Delivery parameters are key for sunscreen use, preventing skin cancer and research. • Standardization of models, conditions and endpoints key for future sunscreen testing. • In vitro assay results vary considerably. • Innovation is needed to develop in vitro sunscreen delivery and safety assays that closely align with volunteer outcomes.
Measles outbreak in Dubrovnik-Neretva County, Croatia, May to June 2018
Authors: Morana Tomljenovic, Mato Lakic, Tatjana Vilibic-Cavlek, Sanja Kurecic Filipovic, Vesna Visekruna Vucina, Andrea Babic-Erceg, Miljenko Ljubic, Iva Pem Novosel, Maja Ilic, Irena Tabain, Jelena Ivancic-Jelecki, Lisa Hansen, Bernard Kaic
Journal: Eurosurveillance (2020)

In May 2018, measles was introduced in the Dubrovnik region by an adult who recently travelled to Kosovo*. Control measures and an outbreak investigation were implemented: 15 epidemiologically-linked cases met the outbreak case definition of a visitor/resident of Dubrovnik-Neretva County with laboratory-confirmed measles and symptom onset beginning on May 19. New cases were identified through hospitals and primary care physicians. Throat swabs, urine and/or serum samples were collected from outbreak cases. RT-PCR detection of viral RNA and IgM/IgG was used to confirm infection. The median age of cases was 33 years, with one 8 month-old infant. Vaccination status was unknown for 9 cases, three were unvaccinated, one case had history of one dose and two cases reported receiving two doses of measles-containing vaccine. There were 11 hospitalisations and one person developed pneumonia. Control teams undertook an extensive search of contacts and implemented a range of control measures. Despite the outbreak occurring at the beginning of the summer tourism season, it was contained and did not spread to neighbouring regions. With continuing measles transmission in Europe, even small outbreaks create a burden on the health system in countries which have eliminated measles, and illustrate the importance of maintaining high immunisation coverage.
Tenofovir Rescue Therapy Achieves Long-Term Suppression of HBV Replication in Patients with Multi-Drug Resistant HBV: 4 Year Follow-Up of the TDF109 Cohort
Authors: Lucy Y Lim, Scott Patterson, Jacob George, Simone I Strasser, Alice U Lee, William Sievert, Amanda J Nicoll, Stuart K Roberts, Paul V Desmond, Scott Bowden, Alexander J Thompson, Stephen Locarnini, Peter W Angus
Journal: Hepatology (2012)
Transforming growth factor–β in tissue fibrosis
Authors: Nikolaos G. Frangogiannis
Journal: The Journal of Experimental Medicine (2020)

TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.
rhIGF-1/BP3 Preserves Lung Growth and Prevents Pulmonary Hypertension in Experimental Bronchopulmonary Dysplasia
Authors: Gregory Seedorf, Christina Kim, Bradley Wallace, Erica W. Mandell, Taylor Nowlin, Douglas Shepherd, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Antenatal factors, such as chorioamnionitis, preeclampsia, and postnatal injury, are associated with an increased risk for bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) after preterm birth. IGF-1 (insulin-like growth factor-1) is markedly decreased in normal preterm infants, but whether IGF-1 treatment can prevent BPD or PH is unknown.
Outcomes of patients with high-risk non-muscle invasive bladder cancer (NMIBC) who undergo radical cystectomy after BCG and subsequent salvage intravesical therapy.
Authors: Vignesh T. Packiam, Craig V. Labbate, Stephen A. Boorjian, Robert F. Tarrell, Brittany Adamic, Mohammad Mahmoud, Matvey Tsivian, Svetlana Avulova, John Cheville, R. Jeffrey Karnes, Matthew K. Tollefson, Ryan P. Werntz, Gary D. Steinberg, Igor Frank
Journal: Journal of Clinical Oncology (2020)

483 Background: We evaluate the impact of salvage intravesical therapy on survival in patients with NMIBC previously treated with BCG who ultimately underwent radical cystectomy (RC). Methods: We retrospectively identified patients with NMIBC who received at least 1 complete induction course of BCG and subsequently underwent RC for bladder cancer between 2000-2018. Patients were stratified by receipt of salvage intravesical therapy following BCG prior to RC. Oncologic outcomes were compared using Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: We identified 371 patients who underwent RC after receiving BCG, of whom 55 (15%) received salvage intravesical therapy, most commonly Mitomycin C (n = 26), Valrubicin (n = 8), Gemcitabine (n = 7), and CG0070 (n = 6). Median follow-up among survivors was 1.1 (IQR 0-4.3) years. Patients who received salvage intravesical therapy were more likely to initially present with CIS (27% vs 17%) and less likely to present with T1 disease (33% vs 50%, both p &lt; 0.05). Receipt of salvage intravesical therapy was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (33% vs 41%, p = 0.27). Furthermore, on Kaplan-Meier analysis, receipt of salvage intravesical therapy was not associated with cancer-specific or overall survival. On multivariable Cox proportional hazards regression, clinical stage prior to RC, but not receipt of salvage intravesical therapy, was associated with inferior cancer-specific survival and overall survival. Conclusions: Our results suggest that RC following carefully managed salvage intravesical therapy after BCG is not associated with inferior oncologic outcomes, which can improve patient counseling. [Table: see text]
Oncofid-P-B for the treatment of BCG unresponsive carcinoma <i>in situ</i> (CIS) of bladder: Results of European multicenter phase I study at the end of 12- consecutive weeks intensive course.
Authors: Rodolfo Hurle, Giorgio Ferruccio Guazzoni, Piergiuseppe Colombo, Armando Santoro, Ottavio De Cobelli, Ettore Di Trapani, Gloria Nohales, Llorente Carlos, Ramon Duran-Merino, Massimo Lazzeri
Journal: Journal of Clinical Oncology (2020)

486 Background: There is an unmet clinical need for new drugs able to delay or avoid cystectomy in patients with CIS unresponsive to BCG. Here, we report the safety and efficacy of Oncofid − P-B, is a new drug that originates from the chemical conjugation of paclitaxel with hyaluronic acid, in patients with CIS unresponsive or intolerant to BCG. Methods: This is an open-label, single arm, multicenter international study (Registered as EudraCT Number: 2016-004144-11) to assess safety, tolerability and efficacy of Oncofid-P-B administered in 20 patients with CIS, unresponsive or intolerant to BCG and unwilling or unfit for cystectomy. Oncofid-P-B was administered by intravesical instillation for 12 consecutive weeks (intensive phase). A 12 monthly (maintenance phase) in patients who were in complete response (CR) after the intensive phase is ongoing. The primary end-point was the overall safety profile. Secondary endpoints included i) efficacy after the intensive phase ii) compliance, iii) systemic absorption. The CR is defined as a negative cystoscopy including biopsy of the urothelium and negative cytology. Statistics will be calculated, as appropriate, for the quantitative variables. Results: Of the 20 enrolled patients who completed the intensive phase, CR was achieved in 15 patients (75%). Seven G1-G2 drug-related adverse events (AEs) were reported in only three patients over 240 instillations. No drug related serious AEs and no study withdrawal have been reported. In all plasma samples, the drug concentration was always below the Limit of Quantification (0.1ng/ml). Over 15 patients who ended the intensive course without CIS recurrence, five already completed the 12-month maintenance phase (four patients with no recurrence of CIS), thirteen were disease free after three months and six are completing the maintenance. Conclusions: The excellent safety profile of Oncofid-P-B is well positioned as compared with the most recent competitors, thus confirming its potential as therapeutic option in BCG unresponsive CIS patients, also with a prolonged treatment schedule, and deserves further clinical evaluation. Clinical trial information: 2016-004144-11.
Advances in clinical trial design: Weaving tomorrow’s TB treatments
Authors: Christian Lienhardt, Andrew Nunn, Richard Chaisson, Andrew A. Vernon, Matteo Zignol, Payam Nahid, Eric Delaporte, Tereza Kasaeva
Journal: PLoS Medicine (2020)

The development process for new tuberculosis (TB) regimens remains slow and costly.In this concluding paper of the PLOS Medicine Special Collection, we highlight the key suggestions made at a WHO Technical Consultation on "Advances in Clinical Trial Design for Development of New TB Treatments" held in 2018 to address this challenge.• Pharmacokinetics and pharmacodynamics (PK-PD) properties of candidate drugs are critical for constructing effective combination regimens.Bridging PK-PD methods to the analysis of Phase II studies and integrating longitudinal culture results would help with clarifying dose-response relationships and to link drug exposure to bactericidal activity; this would provide valuable insights for the identification of the components of suitable regimens.• New adaptive designs can accelerate Phase II and III trials and improve our ability to select regimens early for further investigation.Among these, the integration of extended posttreatment follow-up with collection of real-time treatment outcomes in the new hybrid Phase IIC design, with features drawn from both Phase II and Phase III trials, permits earlier identification of candidate regimens likely to succeed in Phase III.• Once the efficacy of a regimen is demonstrated in high-quality randomized controlled trial(s), the assessment of its effectiveness under programmatic conditions may permit an estimation of the amount of nonadherence that could substantially alter the likelihood of treatment success.• Vulnerable populations, such as children, pregnant women, and people with HIV infection, should be included in clinical trials from the outset, as these groups have unique characteristics regarding PK, safety, and efficacy, which necessitate special attention in drug and regimen development.• We advocate here for a better systematization and harmonization of the approaches taken internationally to ensure that best practices and novel research designs are used to accelerate development of new TB regimens.By using all the creative approaches
Linking the <i>Aggressive Variant Prostate Cancer</i> (AVPC) molecular signature (-ms) to androgen indifference in a prospective clinical trial.
Authors: Paul Vincent Viscuse, Miao Zhang, Jingjing Liu, Rebecca Slack Tidwell, Sumit Kumar Subudhi, Amado J. Zurita, Paul Gettys Corn, Shi-Ming Tu, John C. Araujo, Jennifer Wang, Eleni Efstathiou, Jianbo Wang, Patrick Glen Pilie, Patricia Troncoso, Jianhua Zhang, Christopher Logothetis, Ana Aparicio
Journal: Journal of Clinical Oncology (2020)

156 Background: AVPC are morphologically heterogeneous tumors that share clinical features with the rare, virulent, androgen-indifferent and platinum-sensitive, small cell histologic variant. The AVPC-ms is composed of ≥2 defects in TP53, RB1 and PTEN, is detectable in »30% of advanced prostate cancers and predicts for benefit from platinum combinations (Corn et al. Lancet Oncol, 2019). Preclinical studies link the AVPC-ms with androgen indifference, but a prospective clinical association with decreased sensitivity to androgen signaling inhibitors is lacking. Methods: In a phase II trial (NCT02703623), men with metastatic castration resistant prostate cancer (mCRPC) treated with abiraterone and apalutamide were classified at week 8 as having a ‘satisfactory’ decline in PSA (≥ 50% from baseline) and CTC (≤5/7.5mL) or ‘unsatisfactory’. Pretreatment biopsies were obtained for immunohistochemistry (IHC) for TP53, RB1 and PTEN and RNA sequencing. Results: 198 men were registered. 59 (31.5%) of 187 evaluable had ‘unsatisfactory’ marker declines. Age, race/ethnicity, and baseline ECOG, PSA and LDH were similar between the groups. Men in the ‘unsatisfactory’ group had higher median total alkaline phosphatase (120 vs. 86; p=0.002), bone-specific alkaline phosphatase (21 vs. 16; p=0.01), CTC (9 vs. 1; p&lt;0.001), and urine n-telopeptides (338.5 vs 182.5; p=0.003) levels. Unsupervised clustering of RNA profiles from 45 tumor biopsies revealed two distinct clusters. The top enriched gene set (FDR q-val&lt;0.000) included ‘epithelial mesenchymal transition’, ‘E2F targets’ and ‘G2M checkpoint’ genes in one (n=18) and ‘androgen response’ in another (n=27) cluster. Six (33.3%) and 9 (33.3%) of the samples respectively belonged to patients in the ‘unsatisfactory’ decline group. IHC and RNA sequencing of the remaining samples are ongoing. Conclusions: Signaling pathways associated with androgen indifference can be identified in the tumor biopsies of men with early mCRPC, prior to exposure to secondary androgen signaling inhibitors. Their association with the AVPC-ms and patient outcomes will be presented. If confirmed, these markers could be used to inform therapy selection. Clinical trial information: NCT02703623.
Clinical Activity of AK002, an Anti-Siglec-8 Monoclonal Antibody, in Treatment-Refractory Chronic Urticaria
Authors: Sabine Altrichter, Petra Staubach, Malika Pasha, Henrik Rasmussen, Bhupinder Singh, Alan Chang, Jonathan Bernstein, Frank Siebenhaar, Marcus Maurer
Journal: Journal of Allergy and Clinical Immunology (2020)
Association of circulating tumor cell chromosomal instability with worse outcomes in men with mCRPC treated with abiraterone or enzalutamide.
Authors: Landon Carter Brown, Susan Halabi, Joseph Schonhoft, Jun Luo, David M. Nanus, Paraskevi Giannakakou, Russell Zelig Szmulewitz, Daniel Costin Danila, Patrick Healy, Monika Anand, Jason Somarelli, Howard I. Scher, Rick Wenstrup, William R. Berry, Scott T. Tagawa, Emmanuel S. Antonarakis, Daniel J. George, Andrew J. Armstrong
Journal: Journal of Clinical Oncology (2020)

183 Background: While AR-V7 is a known driver of hormonal resistance, most men with mCRPC lack AR-V7 detection and commonly experience cross-resistance to abiraterone and enzalutamide (abi/enza). Loss of AR dependence through neuroendocrine (NE) differentiation or chromosomal instability (CIN) may explain AR therapy cross-resistance in additional men. Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. We assessed Epic CTC AR-V7, CIN and NE phenotypes before abi/enza and at progression. Radiographic/clinical progression free survival (PFS) and overall survival (OS) were associated with CIN (&gt;3 CTCs) and NE (&gt;3 CTCs) CTC phenotypes using the proportional hazards model adjusting for Cellsearch CTC, AR-V7, and clinical risk score. Results: 118 men with mCRPC starting on abi/enza were enrolled; 106 had evaluable CTCs for AR-V7, CIN, and NE on the Epic platform. Of these, 22.6% and 9.4% of men exhibited high CTC CIN and NE scores, respectively. High pre-treatment CIN and NE phenotypic scores were observed in 63 and 27% of AR-V7 (+) and in 17 and 7% of AR-V7 (-) men. CTC CIN phenotype but not NE phenotype was associated with a lower confirmed PSA response rate and OS (TABLE) with abi/enza, adjusting for CTC number, AR-V7 and risk score. Conclusions: A high chromosomal instability CTC phenotype is associated with worse outcomes in men with mCRPC treated with abi/enza and warrants further study as a prognostic or predictive biomarker. Clinical trial information: NCT02269982. [Table: see text]
Gastrointestinal (GI) Adverse Events (AEs) Observed With Berotralstat (BCX7353) Treatment for Hereditary Angioedema (HAE) are Primarily Mild, Self-limited, and Diminish with Time on Treatment
Authors: Douglas Johnston, William Lumry, Aleena Banerji, Emel Aygoren-Pursun, Jonathan Bernstein, Marcus Maurer, Marco Cicardi, Sandra Christiansen, Bruce Zuraw, Sylvia Dobo, Paula Busse, Huamin Li, Melanie Cornpropst, Heather Iocca, Eniko Nagy, Sharon Murray, Philip Collis, William Sheridan, Marc Riedl
Journal: Journal of Allergy and Clinical Immunology (2020)
Issues and Questions Surrounding Screening for Cognitive Impairment in Older Patients
Authors: Ronald C. Petersen, Kristine Yaffe
Journal: JAMA (2020)

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Identification of genomic alterations in signaling pathways associated with poor survival in newly diagnosed metastatic prostate cancer (mCSPC) using artificial intelligence (AI).
Authors: Edwin Lin, Sergiusz Wesolowski, Roberto Nussenzveig, Taylor Ryan McFarland, Umang Swami, Benjamin Louis Maughan, Mark Yandell, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

169 Background: Although the survival outcomes for patients with mCSPC has improved over the last 5 years, disease remains universally fatal even with improved therapies. Currently, genomic information from the tumor is not taken into account for treatment selection and prognostication. AI is increasingly being used in clinical cancer genomics research. Probabilistic Graphical Models (PGMs) are AI algorithms that capture multivariate, multi-level dependencies in complex patterns in large datasets while retaining human interpretability. We hypothesize that PGMs can establish correlation of baseline somatic genomic alteration with poor survival outcomes in mCSPC. Methods: Eligible men had new mCSPC starting systemic therapy and had tumor genomic profiling done through a CLIA certified lab. Gene alterations with known pathogenicity were grouped into canonical pathways. Multilevel associations between survival, clinical variables (including baseline PSA, Gleason ≥ 8, and visceral metastasis), and genomic signatures (PI3K/AKT/mTOR, HRR, G1/S Cell Cycle, SPOP, TP53, WNT, and MYC) were assessed using a Bayesian Network (BN), and confidence intervals were estimated by bootstrapping. A Kaplan-Meier (KM) survival analysis was performed independently to support the results generated by the BN. Results: Among all variables, only genomic alterations in TP53 and the G1/S pathway were significantly associated with poor overall survival by BN analysis. KM analysis showed concordant results for TP53 (median OS, altered 50 mos vswild-type 84 mos; HR=2.79, 95% CI 1.63 – 4.80; P=0.0002) and G1/S (median OS altered 23 mos vswild-type 73 mos; HR=8.21, 95% CI 3.40 – 19.86; P&lt;0.0001). Conclusions: These hypothesis-generating data reveal genomic signatures associated with poor survival in mCSPC patients. Our results, after external validation, may aid with counseling and treatment selection, as well as patient stratification in future trials in mCSPC.
Genetic Diversity and Thermal Performance in Invasive and Native Populations of African Fig Flies
Authors: Aaron A Comeault, Jeremy Wang, Silas Tittes, Kristin Isbell, Spencer Ingley, Allen H Hurlbert, Daniel R Matute
Journal: Molecular Biology and Evolution (2020)

Abstract During biological invasions, invasive populations can suffer losses of genetic diversity that are predicted to negatively impact their fitness/performance. Despite examples of invasive populations harboring lower diversity than conspecific populations in their native range, few studies have linked this lower diversity to a decrease in fitness. Using genome sequences, we show that invasive populations of the African fig fly, Zaprionus indianus, have less genetic diversity than conspecific populations in their native range and that diversity is proportionally lower in regions of the genome experiencing low recombination rates. This result suggests that selection may have played a role in lowering diversity in the invasive populations. We next use interspecific comparisons to show that genetic diversity remains relatively high in invasive populations of Z. indianus when compared with other closely related species. By comparing genetic diversity in orthologous gene regions, we also show that the genome-wide landscape of genetic diversity differs between invasive and native populations of Z. indianus indicating that invasion not only affects amounts of genetic diversity but also how that diversity is distributed across the genome. Finally, we use parameter estimates from thermal performance curves for 13 species of Zaprionus to show that Z. indianus has the broadest thermal niche of measured species, and that performance does not differ between invasive and native populations. These results illustrate how aspects of genetic diversity in invasive species can be decoupled from measures of fitness, and that a broad thermal niche may have helped facilitate Z. indianus’s range expansion.