tbuckley/cabot-search huggingface dataset:
Challenges to Behavioral Health and Injury Surveillance During the COVID-19 Pandemic
Authors: Michael Schoenbaum, Lisa Colpe
Journal: JAMA Psychiatry (2021)

Kristin M. Holland, PhD, MPH; Christopher Jones, PharmD, DrPH, MPH; Alana M. Vivolo-Kantor, PhD, MPH; Nimi Idaikkadar, MPH; Marissa Zwald, PhD; Brooke Hoots, PhD; Ellen Yard, PhD; Ashley D'Inverno, PhD; Elizabeth Swedo, MD; May S. Chen, PhD; Emiko Petrosky, MD; Amy Board, PhD; Pedro Martinez, MPH; Deborah M. Stone, ScD; Royal Law, PhD; Michael A. Coletta, BS; Jennifer Adjemian, PhD; Craig Thomas, PhD; Richard W. Puddy, PhD; Georgina Peacock, MD; Nicole F. Dowling, PhD; Debra Houry, MD
Diagnostics of Pulmonary Aspergillosis in Critically Ill Hematological and Non-Hematological Patients in the Intensive Care Unit By Combined Use of Galactomannan, 1-3-Beta-D-Glucan, Aspergillus Specific PCR and Conventional Culture in Concurrent Blood and Bronchoalveolar Lavage Samples — Results of a Multicenter Prospective Pilot Study
Authors: Tobias Boch, Birgit Spiess, Tobias Liebregts, Peter Schellongowski, Patrick Meybohm, Peter-Michael Rath, Jörg Steinmann, Simone Britsch, Jabbour Claude, Julia Michels, Wolf-Karsten Hofmann, Mark Reinwald, Dieter Buchheidt
Journal: Blood (2017)
Oncologists’ views on Expanded Access and Right-to-Try: The need for education and shared decision-making.
Authors: Zubin Master, Cambray Smith, Jeremiah Stout, Alex A. Adjei, Jan C. Buckner, Jon Charles Tilburt
Journal: Journal of Clinical Oncology (2021)

e13603 Background: Over half of Americans report favoring access to experimental treatments even if they have yet to be proven either safe or effective, yet only 3-5% are enrolled in clinical trials and a fraction of a percent in expanded access. The Expanded Access (EA) program (aka “compassionate use”) and Right-to-Try (RTT) are parallel federal mechanisms that offer qualifying patients access to off-trial experimental treatments. Our study aimed to capture the views and experiences of oncologists on obtaining eligible medicine using the FDA’s EA and is the first to report findings on physician attitudes toward RTT. Methods: We conducted 21 semi-structured interviews and qualitative analysis of oncologists at a major cancer center with 3 main sites across the U.S. Participants were purposely selected to have experience with EA. Results: Oncologists’ considerations for offering EA options to patients were based on a sound scientific rationale, reasonable risk-benefit ratio, functional status of the patient, and patient motivation. Although oncologists’ experience positively correlated with level of ease in navigating EA, most remained largely unfamiliar with RTT. Only 4 oncologists had experience discussing RTT with patients and none had obtained an experimental therapeutic under this pathway. When informed about RTT, oncologists articulated 3 sets of concerns including limited safety and oversight, unclear structure and lack of requirements to collect and report data, and the potential for inflating patient expectations. Published work by others have shown that patients desire experimental options to be offered and report that physicians do not always offer experimental medicine taking into account factors, such as, reimbursement. Given that oncologists may factor in variables such as patient motivation, and potentially affordability or health literacy, when considering whether experimental medicine is appropriate to offer their patient, there may be a need to develop a conversation aid so that clinically relevant options are presented to patients equitably and patient choice is enhanced. Conclusions: Further research to better understand patient perspectives and potential discordant views between patients and oncologists is needed in order to design shared decision-making tools to inform oncologists about off-trial preapproval pathways and help both oncologists and patients navigate the thorny issues of experimental oncology.
Effectiveness of mRNA COVID-19 vaccines in preventing SARS-CoV-2 infections and COVID-19 hospitalisations and deaths in elderly long-term care facility residents, Spain, weeks 53 2020 to 13 2021
Authors: Clara Mazagatos, Susana Monge, Carmen Olmedo, Lorena Vega, Pilar Gallego, Elisa Martín-Merino, María José Sierra, Aurora Limia, Amparo Larrauri
Journal: Eurosurveillance (2021)

Residents in long-term care facilities (LTCF) experienced a large morbidity and mortality during the COVID-19 pandemic in Spain and were prioritised for early COVID-19 vaccination. We used the screening method and population-based data sources to obtain estimates of mRNA COVID-19 vaccine effectiveness for elderly LTCF residents. The estimates were 71% (95% CI: 56–82%), 88% (95% CI: 75–95%), and 97% (95% CI: 92-99%), against SARS-CoV-2 infections (symptomatic and asymptomatic), and COVID-19 hospitalisations and deaths, respectively.
Antimigratory effect of berberine in T98G, U87MG and primary glioma cell culture.
Authors: Irina V. Mezhevova, Svetlana Yu. Filippova, Sofia V. Timofeeva, Anastasia O. Sitkovskaya, Tatiana V. Shamova, Yaroslav S. Enin, Oleg N. Burov, Viktoria V. Pozdnyakova, Olga Khokhlova, Tatiana F. Pushkareva, Stanislav S. Mezentsev, Inna A. Novikova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2021)

e15045 Background: Berberine is an alkaloid compound with a structure that is highly similar to that of intercalating agents. It affects numerous cell signaling pathways and is widely studied as potential anticancer drug. It is known that berberine affects cancer cells migration through metalloproteinase-2 inhibition, but this effect was never studied on glioma cells. Anti-migratory drugs are of special interest in brain cancer therapy since glioma's highly invasive nature makes total surgical removal of tumor practically impossible. The aim of the study was to evaluate berberine anti-migratory activity on glioma cells. Methods: Cell migration capacity of T98G and U87MG cell lines, as well as primary glioma cell culture established in our laboratory, was assessed via standard wound healing assay with automated image acquisition and analysis on Lionheart FX (BioTek) cell imager. Prior to assay setting up cell cultures were maintained in DMEM medium with L-glutamine (1 μM) (Gibco) and 10% FBS (Gibco) at 37C 0 and 5.0% CO 2 . Cells were seeded at 250 000 cells per well on 24-well plates and incubated overnight in order to attach to plate bottom. After that a vertical wound was made manually in each well, and berberine was added to experimental wells to final concentration 50 mg/L. Plates with cells were continuously incubated and photographed in cell imager at 37C 0 and 5.0% CO 2 . The extent of cells migration was measured as the percent of wound area decrease after 24 hours of incubation in relation to starting time point. Data are given as: Mean ± 95% confidence interval. Results: In our study we berberine exhibited anti-migratory activity in all cell cultures under study. In rather fast growing primary cell culture wound area decrease was 99.23%±0.62% in control sample and 91.75%±0.28% in experimental sample. The difference was small but significant at p &lt; 0.001 level (df = 30). Popular permanent glioma cell lines T98G and U87MG showed more prominent decrease in studied parameter with higher degree of variance at the same time. In T98G wound area decrease was 71.6%±12.3% in control and 48.8%± 7.6% in experimental samples after 24 hours of cultivation in presence of 50 mg/L berberine. While U87MG demonstrated 60.28%±5.13% and 37.5%± 8.34% wound area decrease accordingly. The obtained difference between control and experimental groups in permanent cell cultures was statistically significant at the 0.05 level (df = 30). Conclusions: Our preliminary research proved berberine to be potent anti-migratory agent in glioma treatment. Further investigations are needed to evaluate its ability to inhibit glioma cell expansion in vivo.
Oncogenic FGFR3 gene fusions in solid tumors among Chinese cancer patients.
Authors: Libin Xu, Ming Liu, Jingxian Duan, Tao Wang
Journal: Journal of Clinical Oncology (2021)

e15072 Background: Oncogenic FGFR3 (fibroblast growth factor receptor 3) gene fusions have been identified as driver mutations that lead to the activation of FGFR3 in many solid tumor types and serve as a novel therapeutic target for FGFR inhibitors in clinical development. TACC3 (transforming acid coiled coil 3) is the most common partner of these FGFR3 fusions. Methods: The study enrolled over ten thousand cases of Chinese patients with different types of solid tumors. We performed targeted sequencing assay with our 605 gene panel that covered all the exon and intron regions of the FGFR3 gene, so that we could identify nearly all the FGFR3 translocation events. Results: The prevalence and form of FGFR3 fusions in different tumor types were shown in Table. We identified seven patients harboring FGFR3 fusion events, with six cases of FGFR3-TACC3 and one case of FGFR3-UBE2K. In the seven patients, three of them were also harbored concomitant TP53 gene mutations, and six of them were microsatellite stability (MSS), and one was microsatellite instability-low (MSI-L). Conclusions: FGFR3 gene rearrangements were identified in different solid tumor types in our study, and they were relatively rare compared to other novel mutations. However, clinical testing for the identification of FGFR3 fusions should be prioritized in bladder cancer patients. Consistent with other studies, the most common FGFR3 fusion form was FGFR3-TACC3. Co-occurring genetic alterations in FGFR3 gene fusions cases were also common. From our limited number of cases, most of FGFR3 gene fusions patients were MSS.[Table: see text]
Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.
Authors: Mat Robinson, Kevin Vervier, Amy Popple, Simon Harris, Robyne Hudson, David Adams, Roy Rabbie, Doreen Milne, Catherine Booth, Sarah Joanne Welsh, David Bruce, Philippa Gail Corrie, Trevor Lawley
Journal: Journal of Clinical Oncology (2021)

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.
Long-term results of the GEINO 1401 TRIAL: Randomizing patients to stop or to continue temozolomide until 12 cycles.
Authors: Marta Domenech, Carles Fabregat-Franco, Carlos Mesia, Anna Esteve, Sonia Del Barco Berron, Estela Pineda, Regina Gironés Sarrió, Ramon De las peñas, Jose Fuster, L Miguel Navarro, Miriam Alonso, Clara Olier, Pedro Perez, Alfonso Berrocal, Marta Covela Rúa, Ainhoa Hernandez Gonzalez, Cristina Carrato, Carolina Sanz, José Manuel Sepulveda Sánchez, Carmen Balana
Journal: Journal of Clinical Oncology (2021)

2013 Background: We previously presented our results of the GEINO 1401 trial that randomized patients diagnosed with glioblastoma and treated with chemoradiotherapy and adjuvant temozolomide (TMZ) followed by six cycles of TMZ, to receive an extended use of TMZ up to 12 cycles or to control. We found no differences in 6-months neither progression free survival (PFS) nor overall survival (OS). In this report we actualize our results and analyse long-term survivor patients (LTSP). Methods: The trial NCT02209948 randomized (ratio 1:1) 159 patients diagnosed with glioblastoma who had been treated with standard therapy to stop treatment or to continue up to 12 cycles of TMZ. Patients were stratified based on their O6-methylguanine-DNA-methyltransferasa (MGMT) methylation status and presence or absence of measurable disease at inclusion. We update here OS outcomes and analyse the data of LTSP defined as an OS over 30 months from diagnosis. Results: At a median follow-up of 20 months, 82.4% of the patients had died and 89.9% had progressed. The median OS from randomization was 22.0 months for the control arm and 18.2 for the experimental arm: HR 0.957 (95%CI 0.806-1.136, p = 0.615). At 2 years from randomization there were a 61% of survivors in the TMZ group and 62% in the control group. There were a 49.7% of LTSP showing no differences between TMZ and control group. We found a higher prevalence of methylated MGMT in LTSP, but no differences were shown in patients with or without measurable disease at inclusion, status of IDH and the use of bevacizumab after progression. Conclusions: Adding 6 cycles of TMZ after the first 6 adjuvant cycles confers no additional benefit in OS. Nearly 50% of the patients included in GEINO 1401 who had been previously treated with TMZ 6 cycles without progressing were LTSP. Clinical trial information: NCT02209948.
Demalonylation of DDX3 by Sirtuin 5 promotes antiviral innate immune responses
Authors: Xingying He, Tianliang Li, Kewei Qin, Shiyuan Luo, Zhenjie Li, Qingqing Ji, Honghao Song, Huyang He, Hao Tang, Chaofeng Han, Hongjiao Li, Yan Luo
Journal: Theranostics (2021)

Rationale: Hosts defend against viral infection by sensing viral pathogen-associated molecular patterns and activating antiviral innate immunity through TBK1-IRF3 signaling. However, the underlying molecular mechanism remains unclear. Methods: SiRNAs targeting Sirt1-7 were transfected into macrophages to screen the antiviral function. Sirt5 deficient mice or macrophages were subjected to viral infection to assess in vivo and in vitro function of Sirt5 by detecting cytokines, viral replicates and survival rate. Immunoprecipitation, WesternBlot and luciferase reporter assay were used to reveal molecular mechanism. Results: In this study, we functionally screened seven Sirtuin family members, and found that Sirtuin5 (Sirt5) promotes antiviral signaling and responses. Sirt5 deficiency leads to attenuated antiviral innate immunity in vivo and in vitro upon viral infection by decreasing TBK1-IRF3 activation and type I IFN production. Sirt5 overexpression increased antiviral innate immunity. Mechanism investigation revealed that Sirt5 interacts with DDX3 and demalonylates DDX3, which is critical for TBK1-IRF3 activation. Mutation of the demalonylation lysine sites (K66, K130, and K162) of DDX3 increased ifnβ transcription. Furthermore, the acetylation on lysine 118 of DDX3 positively regulated ifnβ transcription, whereas Sirt5 could not deacetylate this site. Conclusion: Sirt5 promotes anti- RNA and DNA virus innate immune responses by increasing TBK1 signaling through demalonylating DDX3, which identifies a novel regulatory pathway of antiviral innate immune response.
Efficacy of anti-PD(L)1 therapy for patients (Pts) with advanced urothelial carcinoma (aUC) with primary resistance to platinum-based chemotherapy (PC).
Authors: Tyler F. Stewart, Nikhil V. Kotha, Hannah Elizabeth Dzimitrowicz, Dimitrios Makrakis, Ali Raza Khaki, Nicholas I. Simon, Ariel Ann Nelson, Dory Freeman, Tracy L Rose, Wolfgang Beck, Neal Shiv Chawla, Sumanta K. Pal, Deepak Kilari, Matthew I. Milowsky, Andrea B. Apolo, Petros Grivas, Tian Zhang, Guru P. Sonpavde, Rana R. McKay
Journal: Journal of Clinical Oncology (2021)

e16515 Background: PC remains standard first-line (1L) therapy for aUC. Approximately 15% of pts exhibit primary resistance (P-R) to PC and ∼25% progress by 4 months. PD(L)1 inhibitors yield objective response rates (ORR) of ∼20% in pts with progression after PC; however, it is unclear if this benefit extends to pts with P-R to PC. We examined the efficacy of anti-PD(L)1 in pts with aUC who experienced P-R to 1L PC. Methods: We conducted a multi-institutional retrospective study of pts with aUC who experienced P-R to PC and were subsequently treated with single-agent anti-PD(L)1 therapy. Eligibility included pts with unresectable or metastatic disease diagnosed after January 1, 2017. P-R to PC was defined as radiographic progression by RECISTv1.1 within 12 weeks from initiation of PC. Pts who developed metastatic disease while receiving (neo)adjuvant PC were eligible. Clinicopathologic variables were collected. ORR to anti-PD(L)1 was the primary endpoint. Secondary endpoints included time to treatment failure (TTF, defined as time from start of anti-PD(L)1 therapy to next line of therapy, hospice or death) and overall survival (OS) were estimated using Kaplan-Meier method. Multivariate (MV) analysis using Cox regression evaluating factors associated with OS was performed. Results: Overall, 42 pts were included: 74% male, median age 65 (28-90); 79% ever smokers; 21% mixed histology; 31% received definitive locoregional therapy. Metastatic sites at diagnosis of aUC included: lymph node only (19%), liver (29%), bone (38%) and lung (33%). At diagnosis of aUC, ECOG PS was 0 in 26%, 1 in 52% and unknown in 21%. 1L PC included cisplatin (76%) and carboplatin (24%) based regimens. Anti-PD(L)1 was received either 2L (98%) or 3L (2%). Overall, ORR to anti-PD(L)1 was 17%: CR (2%), PR (14%), SD (14%), PD (57%) and unknown (12%). Of the 24 pts with PD as best response to anti-PD(L)1, only 9 (38%) received subsequent therapy. Overall, median TTF was 4.2 mo (95% CI 2.8-6.7 mo) and median OS was 7.4 mo (95% CI 4.2-11.1 mo). ORR in patients with a PDL1 combined positive score ≥ 10% (n=6) was 0%: 1 SD and 5 PD. MV analysis for OS from start of anti-PD(L)1 is shown (Table). Conclusions: P-R to PC portends a poor prognosis in pts with aUC. While a subset of patients may respond to anti-PD(L)1 therapy, the majority of pts do not derive benefit. Alternative agents, e.g. antibody drug conjugates and FGFR inhibitors, and combination-therapy should be investigated for this high risk population.[Table: see text]
Apatinib in combination with camrelizumab, a humanized immunoglobulin G4 monoclonal antibody against programmed cell death-1, in patients with metastatic acral melanoma.
Authors: Xuan Wang, Chuanliang Cui, Bin Lian, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Lili Mao, Xue Bai, Bixia Tang, Xieqiao Yan, Siming Li, Li Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2021)

9539 Background: Patients(pts) with metastatic acral melanoma respond poorly to anti–PD-1 monotherapy. Apatinib, a vascular endothelial growth factor (VEGF) inhibitor, is a kind of anti-angiogenic drugs which have shown synergistic therapeutic effects in combination with PD-1 blockade. We conducted this single-center, open label phase trial to evaluate the safety and efficacy of camrelizumab in combination with apatinib in advanced treatment-naïve acral melanoma pts. Methods: Eligible participants were adult pts (aged 18 to 75) with histologically confirmed unresectable stage or distant metastatic acral melanoma. Exclusion criterion included unknown primary melanoma, brain metastatic disease or previous use of anti PD-1 ab. Pts received camrelizumab at 200mg intravenous infusion every 2 weeks, in combination with apatinib 250 mg orally once a day. The primary endpoint was ORR according to RECIST 1.1 criteria, and the secondary endpoints were safety and RFS. Results: Thirty pts were enrolled from April 2019 to January 2021. Basic characteristics: the mean age was 56.7 years, 22 pts were at stage, 33.3% had an elevated LDH level. Median tumor burden was 45mm (10-187). Gene mutation: Nras 4, cKit 3, Braf 2. Up to January 2021, 27 pts could be evaluated, in which 2 pts got CR, 4 pts achieved PR, and 63% experienced tumor shrinkage. The ORR and DCR were 22.2% and 77.8%, respectively. With a median follow up time of 8.3 months, the median PFS was 8.0 months (95% CI, 3.68, 10.19), the one-year durable response rate was 83.3% and the duration of response time was still not reached. Univariate analysis showed high LDH level was negatively associated with PFS. Whole exome data of baseline tumor biopsies revealed a positive correlation between high copy number variation (CNV) plus high mutational load (TMB) and efficacy，and all of the 4pts with MDC1 gene mutation got tumor shrink and 2 got PR. 96.7% pts experienced treatment-related AEs (TRAEs), including hand foot syndrome in 40%, proteinuria in 40%, liver dysfunction in 36.7%, and hypothyroidism in 30%. The grade 3-4 TRAEs were 33.3%. AE-related permanent discontinuation occurred in only 13.3% pts. 6 pts had delays of treatment due to the COVID-19 epidemic. No dose-limiting toxicities and suspected unexpected AEs were observed in the combination. Conclusions: The combination of apatinib plus camrelizumab was tolerable and showed promising antitumor activities and PFS improvement in pts with treatment-naïve metastatic acral melanoma. The survival is still in follow up. Clinical trial information: NCT03955354.