tbuckley/cabot-search huggingface dataset:
The comparison of mutation-based biomarkers for early-stage and advanced-stage non-small cell lung caner.
Authors: Jie Yao, Xiuqin Zhang, Liangbin Pan, Yuxuan Wang, Ke Chen, Jiajun Han, Guocai Mao, Biao Zhang, Nan Wang, Yuange He, Dejian Gu, Rongrong Chen, Haitao Ma
Journal: Journal of Clinical Oncology (2021)

e21176 Background: In recent years, immune checkpoint inhibitors have shown promise in the treatment of advanced-stage non-small cell lung cancer (NSCLC), more and more clinical studies have proved this treatment could also be effective for early-stage NSCLC. It’s confirmed that the count of somatic mutations (SM) and tumor mutation burden (TMB) were related to the effect of immunotherapy for advanced stage tumors but this relationship was not proved in early stage tumors, the inherent difference between early stage and advanced stage cancer is unclear. So we compared the SM count and driver mutation frequency for the ES and AS NSCLC cancer. Methods: We retrospectively analyzed the genetic aberrations in 288 patients of Chinese NSCLC patients. All the patients were detected by hybridization capture-based NGS 1021-gene panel sequencing with tumor tissue and peripheral blood control samples. Results: The genetic alterations in 288 patients with NSCLC were analyzed by defined stage categories, the tumors in clinical stage I-IIIa were classified as early-stage (ES) group and stage IIIb-IV were classified as advanced-stage (AS) group. The results showed that the actionable mutation frequency in driver genes such as EGFR/BRAF/MET/ERBB2/KRAS and structural variations called Fusions in ALK/ROS1/RET/NTRK was different in the two groups but was not statistically significant (Table). The average SM count (9.6 versus 6.25, p=0.0001) and the TMB-high (TMB-H) frequency (3.6% versus 13.2%, p=0.002) was significantly higher in AD group (Table). In other words, the driver mutation frequencies has no significant difference between the ES and AS groups but the AS group showed more somatic mutation count and TMB-H frequency, revealing there were more non-driver mutations in AS tumors. The proved relationship between SM count and TMB and the clinical effect of immunotherapy for advanced-stage patients may inapplicable for early-stage tumors, new biomarkers need to be explored for the immunotherapy of early-stage NSCLC patients. Conclusions: There was no significant variation between the early-stage and advanced-stage patients with driver mutations, but more non-driver mutations in advanced-stage patients. The immunotherapy biomarkers such as somatic mutation count and TMB for advanced-stage tumors could be inapplicable for early-stage tumors. The biomarkers for immunotherapy of early-stage NSCLC patients need further research.[Table: see text]
The impact of pertussis in infants: insights from a hospital-based enhanced surveillance system, Lazio region, Italy, 2016 to 2019
Authors: Elisabetta Pandolfi, Francesco Gesualdo, Caterina Rizzo, Luisa Russo, Ilaria Campagna, Emanuela Carloni, Carlo Concato, Giulia Linardos, Alberto Villani, Sara Ciampini, Antonino Reale, Elena Boccuzzi, Fabio Midulla, Alberto E Tozzi
Journal: Eurosurveillance (2021)

Background Routine surveillance systems for pertussis often suffer from under-recognition and under-reporting. Aim Our aim was to describe the epidemiology and the clinical features of pertussis in children younger than 1 year in an Italian region, detected through an enhanced hospital surveillance system. Methods From 2016 to 2019, we monitored the incidence and the clinical characteristics of hospitalised pertussis cases younger than 1 year in two paediatric hospitals involved in the PERTINENT project. Results We detected 141 pertussis cases, corresponding to an estimated incidence of 105.8 per 100.000 in 2016, 91.7 per 100.000 in 2017, 64.5 per 100.000 in 2018 and 40.9 per 100.000 in 2019, based on the hospitals’ catchment area, roughly corresponding to the Lazio region. A total of 101 cases (77.1%) had a household member with cough or other respiratory symptoms. The most frequent combination of symptoms was paroxysmal cough with apnoea in the absence of fever. Almost 40% had been prescribed an antibiotic treatment before hospitalisation, and the median time from symptom onset to contact with the hospital was 8 days. Thirty-one (22.0%) had complications. Conclusion An enhanced surveillance system showed a high incidence of pertussis among infants in the Lazio region, where the impact of this disease may still be underestimated. Increasing the coverage of pertussis immunisation among pregnant women and improving the capacity for early detection in primary care may contribute to reducing the impact of pertussis among infants.
Penpulimab in combination with anlotinib as first-line treatment in advanced nonsquamous non-small-cell lung cancer.
Authors: Baohui Han, Jianhua Chen, Ziping Wang, Xingya Li, Lin WANG, Lin Wu, Qiang Xie, Yanqiu Zhao, Mengzhao Wang, Junguo Lu, Huaqiu Shi, Feng Ye, Xiaodong Mei, Weirong Yao, Lu Yue, Da Jiang, Jian Zhao, Shucai Zhang, Gongyan Chen, Shunchang Jiao
Journal: Journal of Clinical Oncology (2021)

e21072 Background: Penpulimab is a human IgG1 monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1). Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib significantly improved overall survival in advanced NSCLC patients (pts) in the phase 3 trial ALTER0303. Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced NSCLC pts. This is the trial evaluating chemo-free combination of penpulimab plus anlotinib in treatment-naive advanced NSCLC pts regardless of PD-L1 expression (NCT03866980). Methods: Pts with previously untreated, stage IIIB/IIIC/IV non-squamous NSCLC without sensitizing mutation of the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene were enrolled. Eligible pts received penpulimab 200mg Q3W in combination with anlotinib 12mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included ORR, disease control rate (DCR), duration of response (DoR) and overall survival. Results: As of January 13, 2021, 26 pts had received the combination therapy of penpulimab plus anlotinib (median age 59.5yrs [range 30-71], 76.9% male, 76.9% ECOG PS 1), with a median treatment duration of 3.5 months. Of 21 pts who have had at least one tumor assessment, the ORR was 57.1% (12 PRs) and DCR was 90.5% (12 PRs, 7 SDs). Median PFS has not been reached, and eleven responders remain in response. Treatment-related adverse events (TRAEs) occurred in 53.8% of pts (≥G3 TRAEs occurred in 15.4% [4/26]). Treatment-related SAEs occurred in 15.4% [4/26], and 7.7% of pts [2/26] had drug interruption or discontinuation due to TRAEs. Most common TRAEs (≥15%) were ALT increased, AST increased, hyperthyroidism and hypertension (15.4% each). Conclusions: The combination of penpulimab plus anlotinib as first-line treatment for locally advanced/metastatic NSCLC showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable chemo-free treatment strategy for locally advanced/metastatic NSCLC pts. Clinical trial information: NCT03866980.
Serological analysis reveals an imbalanced IgG subclass composition associated with COVID-19 disease severity
Authors: Jennifer L. Yates, Dylan J. Ehrbar, Danielle T. Hunt, Roxanne C. Girardin, Alan P. Dupuis, Anne F. Payne, Mycroft Sowizral, Scott Varney, Karen E. Kulas, Valerie L. Demarest, Kelly M. Howard, Kyle Carson, Margaux Hales, Monir Ejemel, Qi Li, Yang Wang, Ruben Peredo-Wende, Ananthakrishnan Ramani, Gurpreet Singh, Klemen Strle, Nicholas J. Mantis, Kathleen A. McDonough, William T. Lee
Journal: Cell Reports Medicine (2021)

Coronavirus disease 2019 (COVID-19) is associated with a wide spectrum of disease presentation, ranging from asymptomatic infection to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity and the levels of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, including virus-neutralizing titers. A serological analysis of 536 convalescent healthcare workers reveals that SARS-CoV-2-specific and virus-neutralizing antibody levels are elevated in individuals that experience severe disease. The severity-associated increase in SARS-CoV-2-specific antibody is dominated by immunoglobulin G (IgG), with an IgG subclass ratio skewed toward elevated receptor binding domain (RBD)- and S1-specific IgG3. In addition, individuals that experience severe disease show elevated SARS-CoV-2-specific antibody binding to the inflammatory receptor FcɣRIIIa. Based on these correlational studies, we propose that spike-specific IgG subclass utilization may contribute to COVID-19 disease severity through potent Fc-mediated effector functions. These results may have significant implications for SARS-CoV-2 vaccine design and convalescent plasma therapy.
The covid-19 pandemic took power from the people
Authors: Kamran Abbasi
Journal: BMJ (2021)

Who decides when covid-19 restrictions are lifted? A government might lay out plans for reopening society. It might even emphasise the importance of data, not dates. But, as with any exercise in project management, the milestones tend to loom more powerfully in people’s minds than the objectives. Some scientists now argue that, with the rise of variant B.1.617.2, WHO’s new delta variant, England’s plan for reopening fully on 21 June should be put on hold.12

It’s a debate that will echo around the world. In England, the decision ultimately rests with the prime minister, Boris Johnson, although any remaining confidence in his ability to master the pandemic was dealt a grievous blow by recent testimony from his former aide. …
HGG-40. FOCUSED ULTRASOUND ENHANCES ETOPOSIDE DELIVERY IN A MURINE PONTINE GLIOMA MODEL
Authors: Zachary Englander, Hong-Jian Wei, Antonios Pouliopoulos, Nina Yoh, Nicholas McQuillan, Masih Tazhibi, Tony Wang, Jeffrey Bruce, Peter Canoll, Neil Feldstein, Stergios Zacharoulis, Elisa Konofagou, Cheng-Chia Wu
Journal: Neuro-Oncology (2021)

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with limited treatment options and poor survival. The delivery of systemic therapies in this disease is severely limited by the blood-brain barrier (BBB). Focused ultrasound combined with intravenous microbubbles (FUS+MB) can effectively open the BBB permitting the entry of drugs across the cerebrovasculature. Etoposide is a chemotherapy frequently used in pediatric oncology with well-established anti-tumor effects but limited efficacy when administered systemically in DIPG. Given that FUS+MB in DIPG is not well studied, our goal was to determine the feasibility of ultrasound-mediated BBB opening and etoposide delivery in a preclinical murine pontine glioma model. Methods A syngeneic, orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells into the pons of B6 albino mice. Mice were randomly divided into control (n=6) or FUS+MB groups (n=6). A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier was used with concurrent microbubble injection to sonicate the tumor and its margins on post-injection day 14. Immediately after treatment, 5 mg/kg of intraperitoneal etoposide was administered to all 12 mice. All animals underwent cardiac puncture and blood sampling, followed by transcardiac perfusion and brain harvesting. Liquid chromatography-mass spectometry was performed on both serum and tumor tissue to measure etoposide levels. Results Contrast-enhanced MRI demonstrated successful BBB opening in all FUS+MB mice. Compared to control (mean=20.98ng/g), etoposide concentration in the sonicated tumor tissue (mean=164.77ng/g) was nearly eight times greater. Lastly, the mean brain tumor–to-serum ratio was more than fivefold higher in the treated mice (1.50%) compared with the control mice (0.28%) (P&amp;lt;0.005). Conclusions FUS+MB is hereby shown successful in BBB opening and enhanced delivery of etoposide in a preclinical pontine glioma model.
Abstract NT-100: PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS
Authors: Lu Liu, Shurui Cai, Chunhua Han, Ananya Benerjee, Dayong Wu, Tiantian Cui, Guozhen Xie, Yanfang Zheng, Qi-En Wang
Journal: Clinical Cancer Research (2019)

Abstract Ovarian cancer (OC) is one of the most lethal female malignancy which accounts for just 2.5% of female cancer cases but 5% of deaths because of low survival. 90% of OC are epithelial ovarian cancer (EOC), with an overall 5-year relative survival rate of 47% and only 29% for patients diagnosed with distant-stage. 20% of OC cases are estimated to be due to inherited mutations that confer elevated risk, especially cancer susceptibility genes BRCA1 and BRCA2. PARP inhibitors (PARPi) are novel and promising cancer-targeted drugs. PAPRi are approved by FDA for clinical treatment of advanced EOC patients with BRCA1/2 gene mutation. However, patients gradually gained resistance to PARPi with continuously increased recurrence rate (&amp;gt;90%). Thus, understanding the mechanism underlying PARPi resistance is an urgent need for improving the PARPi efficacy. Aldehyde dehydrogenase (ALDH) activity is considered as a cancer stem cell (CSC) marker and also relative to drug resistance. However, the relationship between ALDH activity and PAPPi resistance remains unclear. In this study, we generated two olaparib-resistant EOC cell lines by continuously treating BRCA2-mutated PEO1 and Kuramochi cell lines for 6 months, and found that these resistant cell lines exhibited higher ALDH activity compared to their corresponding parent cell lines. In addition, short-term treatment of PEO1 and Kuramochi cells with olaparib (7 days) also increased the ALDH+ cell population in these cells, and olaparib-induced ALDH--to-ALDH+ conversion contributed to the expansion of the ALDH+ cell population after olaparib treatment. qRT-PCR analysis demonstrated that ALDH1A1 is the major gene in the ALDH gene family that was induced by olaparib. Overexpression of ALDH1A1 increased olaparib resistance in a panel of EOC cells lines including both BRCA2-muated and BRCA2-wild type cell lines. In summary, our data indicate that olaparib is able to induce ALDH1A1 gene expression, which results in the enhanced ALDH activity. The enhanced ALDH activity can contribute to olaparib resistance in BRCA2-mutated EOC cells. Citation Format: Lu Liu, Shurui Cai, Chunhua Han, Ananya Benerjee, Dayong Wu, Tiantian Cui, Guozhen Xie, Yanfang Zheng, and Qi-En Wang. PARPI-INDUCED ALDH1A1 EXPRESSION CONTRIBUTES TO PARPI RESISTANCE IN OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-100.
4D biofabrication via instantly generated graded hydrogel scaffolds
Authors: Aixiang Ding, Sang Jin Lee, Sriramya Ayyagari, Rui Tang, Cong Truc Huynh, Eben Alsberg
Journal: Bioactive Materials (2021)

Formation of graded biomaterials to render shape-morphing scaffolds for 4D biofabrication holds great promise in fabrication of complex structures and the recapitulation of critical dynamics for tissue/organ regeneration. Here we describe a facile generation of an adjustable and robust gradient using a single- or multi-material one-step fabrication strategy for 4D biofabrication. By simply photocrosslinking a mixed solution of a photocrosslinkable polymer macromer, photoinitiator (PI), UV absorber and live cells, a cell-laden gradient hydrogel with pre-programmable deformation can be generated. Gradient formation was demonstrated in various polymers including poly(ethylene glycol) (PEG), alginate, and gelatin derivatives using various UV absorbers that present overlap in UV spectrum with that of the PI UV absorbance spectrum. Moreover, this simple and effective method was used as a universal platform to integrate with other hydrogel-engineering techniques such as photomask-aided microfabrication, photo-patterning, ion-transfer printing, and 3D bioprinting to fabricate more advanced cell-laden scaffold structures. Lastly, proof-of-concept 4D tissue engineering was demonstrated in a study of 4D bone-like tissue formation. The strategy's simplicity along with its versatility paves a new way in solving the hurdle of achieving temporal shape changes in cell-laden single-component hydrogel scaffolds and may expedite the development of 4D biofabricated constructs for biological applications.
An analysis of lines of treatment and survival analysis in older Indigenous and Nonindigenous women of Western Australia with breast cancer.
Authors: Azim Khan, Lisa Spalding, Hilary Laura Martin, Andrew David Redfern
Journal: Journal of Clinical Oncology (2021)

e12529 Background: Indigenous women with breast cancer (BrCa) have markedly higher mortality and are more likely to be diagnosed with more advanced disease compared with non-indigenous women. However, it is unknown if Indigenous older adults receive same lines of treatment as non-indigenous older adults with breast cancer. Methods: We retrospectively examined data from WA cancer registry from 2001 to 2016 with BrCa by Indigenous status. Indigenous were considered older adults aged above 55 years and non-indigenous aged above 65 years. Cases with confirmed breast cancer, where chemotherapy was indicated in adjuvant and metastatic setting were included for analysis. Overall survival was compared between treatment arms of indigenous and non-indigenous cohort using log-rank analysis and demonstrated by Kaplan Meier curve. Chi-square was employed as well. Results: At time of writing, results were available for 75 indigenous and non-indigenous older adults identified for analysis from cohort of 315 older adults. 79% Indigenous received treatment in adjuvant setting, 14% was not offered and 7% declined adjuvant treatment compared to 89% non-indigenous patients received adjuvant chemotherapy, 7% were not offered and 4% declined therapy. In first line metastatic setting, only 65% older indigenous group received chemotherapy compared to 76% non-indigenous patients. In second line, only 48% patients received treatment compared to 61% non-indigenous patients. In third line, 23% indigenous women received chemotherapy compared to 51% non-indigenous women with significant p-value 0.012. The rate of decline was higher in indigenous cohort. Kaplan meier curve of 10-year survival analysis favors the Non-Indigenous group. The difference between groups was 55 vs 68%. When comparing groups, the median survival of Indigenous group was 79 months and mean survival of Non-Indigenous cohort was 97 months. Log-rank testing p value 0.0025. Conclusions: In this study, indigenous patients have shown reduced survival outcomes and with drop in lines of treatment in the course of disease, highlighting a potential area to address and improve survival outcomes, along with addressing barriers that lead to treatment disparity in older adults.
Lower respiratory tract disease (LRTD) in patients with cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) study.
Authors: Dimpy P Shah, Pankil Shah, Andrew Lachlan Schmidt, Ziad Bakouny, Dimitrios Farmakiotis, Maheen Abidi, Samuel M. Rubinstein, Cesar J. Figueroa, Chris Labaki, Christopher Ryan Friese, Joerg Rathmann, Clara Hwang, Rana R. McKay, Cathleen Park, Matthew Puc, Gayathri Nagaraj, Benjamin French, Jeremy Lyle Warner, Sanjay Shete
Journal: Journal of Clinical Oncology (2021)

6563 Background: Immunodeficiency in patients (pts) with cancer can lead to the progression of common respiratory viral infections to lower respiratory tract disease (LRTD) with potentially high mortality. Understanding risk factors of SARS-CoV-2 related LRTD in pts with cancer is imperative for the development of preventive measures. Methods: We examined all patients aged 18 years or older with cancer and laboratory-confirmed SARS-CoV-2 infection reported between March 16, 2020 and February 6, 2021 in the international CCC19 registry. We examined frequency of LRTD (pneumonia, pneumonitis, acute respiratory distress syndrome, or respiratory failure), demographic and clinicopathologic factors associated with LRTD, and 30-day and overall mortality in pts with and without LRTD. Results: Of 7,289 pts with a median follow-up time of 42 (21-90) days, 2187 (30%) developed LRTD. Pts of older age (65 yrs or older), male sex, pre-existing comorbidities, baseline immunosuppressants, baseline corticosteroids, and ECOG performance status of 2 or more had substantially higher rates of LRTD compared to those without these risk factors (Table). We did not observe differences in LRTD rates between pts of different racial/ethnic groups, smoking history, hypertension, obesity, cancer status, timing or type of anti-cancer therapy. LRTD was more likely in pts with thoracic malignancy (39%), hematological malignancy (39%) compared to those with other solid tumors (27%). The majority of pts (86%) had symptomatic presentation; however, 8% of pts with asymptomatic presentation developed LRTD. 30-day and overall mortality rates were significantly higher in pts with LRTD than those without LRTD (31% vs. 4% and 38% vs. 6%, P &lt; 0.05). Conclusions: COVID-19 related LRTD rate is high and associated with worse mortality rates in pts with cancer. The majority of risk factors associated with LRTD demonstrate underlying immunodeficiency or lung structural damage as a driving force in this population. Identifying pts at high-risk for developing LRTD can help guide clinical management, improve pt outcomes, increase the cost-effectiveness of antiviral therapy, and direct future clinical trial designs for vaccine or antiviral agents.[Table: see text]