tbuckley/cabot-search huggingface dataset:
Combining dietary fibres to reduce intestinal gas production in patients with IBS
Authors: Kristin Verbeke
Journal: Gut (2021)

Consumption of dietary fibre has been associated with multiple beneficial outcomes. For example, it reduces the risk of cardiovascular disease by lowering cholesterol and improving glucose homeostasis, and it improves digestive comfort with looser and more frequent stools. Furthermore, dietary fibre can potentially lower the risk of colon cancer, although evidence from intervention studies supporting the latter is considered insufficient to serve as a basis of guidelines for dietary fibre intake.1 More recent studies indicate that dietary fibre also exhibits immunomodulatory properties and may affect mood and cognition.2

In addition to enhancing bulking in the colon and increasing the viscosity in the intestinal lumen, production of short-chain fatty acids by colonic microbial fermentation is believed to be an important mechanism underlying these health benefits.3 However, fermentation of dietary fibre concomitantly increases the production of gases, in particular hydrogen and to a lesser extent methane and carbon dioxide. Hydrogen primarily results from the reoxidation of reduced pyridine nicotinamide-adenine-dinucleotide (NADH) and flavine-adenine-dinucleotide (FADH) nucleotides, which is essential to maintaining the luminal redox balance. Accumulation of hydrogen, which would restrict further fermentation, is prevented by hydrogenotrophic microbes that convert hydrogen into acetate (acetogens), methane (methanogenic archaea) and sulfate (sulfate-reducing bacteria).4

Patients …
Sports related concussion: an emerging era in digital sports technology
Authors: Dylan Powell, Sam Stuart, Alan Godfrey
Journal: npj Digital Medicine (2021)

Abstract Sports-related concussion (SRC) is defined as a mild traumatic brain injury (mTBI) leading to complex impairment(s) in neurological function with many seemingly hidden or difficult to measure impairments that can deteriorate rapidly without any prior indication. Growing numbers of SRCs in professional and amateur contact sports have prompted closer dialog regarding player safety and welfare. Greater emphasis on awareness and education has improved SRC management, but also highlighted the difficulties of diagnosing SRC in a timely manner, particularly during matches or immediately after competition. Therefore, challenges exist in off-field assessment and return to play (RTP) protocols, with current traditional (subjective) approaches largely based on infrequent snapshot assessments. Low-cost digital technologies may provide more objective, integrated and personalized SRC assessment to better inform RTP protocols whilst also enhancing the efficiency and precision of healthcare assessment. To fully realize the potential of digital technologies in the diagnosis and management of SRC will require a significant paradigm shift in clinical practice and mindset. Here, we provide insights into SRC clinical assessment methods and the translational utility of digital approaches, with a focus on off-field digital techniques to detect key SRC metrics/biomarkers. We also provide insights and recommendations to the common benefits and challenges facing digital approaches as they aim to transition from novel technologies to an efficient, valid, reliable, and integrated clinical assessment tool for SRC. Finally, we highlight future opportunities that digital approaches have in SRC assessment and management including digital twinning and the “digital athlete”.
Stage at cancer diagnosis during the COVID-19 pandemic in western Washington state.
Authors: Catherine R. Fedorenko, Karma L. Kreizenbeck, Li Li, Laura Elizabeth Panattoni, Veena Shankaran, Scott David Ramsey
Journal: Journal of Clinical Oncology (2021)

145 Background: The COVID-19 pandemic disrupted medical care, including routine cancer screening for breast, colorectal, lung and cervical cancers. We aimed to investigate the impact of the pandemic on stage at diagnosis for cancer patients. Methods: Using data from the Washington State SEER records we compared AJCC stage for patients diagnosed with cancer in 2017-2019 to 2020 for two time periods, March to June (initial pandemic months) and July to December (later pandemic months). Patients were included if they were age 18+, diagnosed with a solid tumor, and not diagnosed at autopsy. Results: In the early phase of the pandemic, March – June 2020, there was a shift to cancers being diagnosed at a later stage compared to the same time period in 2017-2019 (Stage III: 13.5% to 14.9%, Stage IV: 16.2% to 19.7%). There was also a decrease in cancer diagnoses for cancers that are often detected through routine screening. As a percentage of all cancer diagnoses, both melanoma (13.2% to 9.8%) and colon cancer diagnoses (7.2% to. 6.7%) decreased during the early pandemic. In the later phase of the pandemic, July to December 2020, the stage at diagnosis showed an indication of returning to pre-pandemic levels with an increase in the proportion of early stage cancers (In situ: 16.6% to 19.3%, Stage I: 38.8% to 41.1%). Stage at diagnosis trends varied by tumor type. For colorectal cancer, the overall number of diagnoses decreased during the initial pandemic months. Stage I diagnoses decreased and Stage IV cancer diagnoses increased in both early and late stages of the pandemic. Conclusions: In Washington State, the COVID-19 pandemic had an impact on stage at diagnosis potentially caused by delays or interruptions in medical care. Additional studies are needed to understand how this shift in stage at diagnosis impacted treatment and outcomes for patients.
Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase
Authors: Hana M El Sahly, Lindsey R Baden, Brandon Essink, Susanne Doblecki-Lewis, Judith M Martin, Evan J Anderson, Thomas B Campbell, Jesse Clark, Lisa A Jackson, Carl J Fichtenbaum, Marcus Zervos, Bruce Rankin, Frank Eder, Gregory Feldman, Christina Kennelly, Laurie Han-Conrad, Michael Levin, Kathleen M Neuzil, Lawrence Corey, Peter Gilbert, Holly Janes, Dean Follmann, Mary Marovich, Laura Polakowski, John R Mascola, Julie E Ledgerwood, Barney S Graham, Allison August, Heather Clouting, Weiping Deng, Shu Han, Brett Leav, Deb Manzo, Rolando Pajon, Florian Schödel, Joanne E Tomassini, Honghong Zhou, Jacqueline Miller
Journal: New England Journal of Medicine (2021)

At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.
All-cause and cause-specific mortality during and following incarceration in Brazil: A retrospective cohort study
Authors: Yiran E. Liu, Everton Ferreira Lemos, Crhistinne Cavalheiro Maymone Gonçalves, Roberto Dias de Oliveira, Andrea da Silva Santos, Agne Oliveira do Prado Morais, Mariana Garcia Croda, Maria de Lourdes Delgado Alves, Julio Croda, Katharine S. Walter, Jason R. Andrews
Journal: PLoS Medicine (2021)

Background Mortality during and after incarceration is poorly understood in low- and middle-income countries (LMICs). The need to address this knowledge gap is especially urgent in South America, which has the fastest growing prison population in the world. In Brazil, insufficient data have precluded our understanding of all-cause and cause-specific mortality during and after incarceration. Methods and findings We linked incarceration and mortality databases for the Brazilian state of Mato Grosso do Sul to obtain a retrospective cohort of 114,751 individuals with recent incarceration. Between January 1, 2009 and December 31, 2018, we identified 3,127 deaths of individuals with recent incarceration (705 in detention and 2,422 following release). We analyzed age-standardized, all-cause, and cause-specific mortality rates among individuals detained in different facility types and following release, compared to non-incarcerated residents. We additionally modeled mortality rates over time during and after incarceration for all causes of death, violence, or suicide. Deaths in custody were 2.2 times the number reported by the national prison administration ( n = 317). Incarcerated men and boys experienced elevated mortality, compared with the non-incarcerated population, due to increased risk of death from violence, suicide, and communicable diseases, with the highest standardized incidence rate ratio (IRR) in semi-open prisons (2.4; 95% confidence interval [CI]: 2.0 to 2.8), police stations (3.1; 95% CI: 2.5 to 3.9), and youth detention (8.1; 95% CI: 5.9 to 10.8). Incarcerated women experienced increased mortality from suicide (IRR = 6.0, 95% CI: 1.2 to 17.7) and communicable diseases (IRR = 2.5, 95% CI: 1.1 to 5.0). Following release from prison, mortality was markedly elevated for men (IRR = 3.0; 95% CI: 2.8 to 3.1) and women (IRR = 2.4; 95% CI: 2.1 to 2.9). The risk of violent death and suicide was highest immediately post-release and declined over time; however, all-cause mortality remained elevated 8 years post-release. The limitations of this study include inability to establish causality, uncertain reliability of data during incarceration, and underestimation of mortality rates due to imperfect database linkage. Conclusions Incarcerated individuals in Brazil experienced increased mortality from violence, suicide, and communicable diseases. Mortality was heightened following release for all leading causes of death, with particularly high risk of early violent death and elevated all-cause mortality up to 8 years post-release. These disparities may have been underrecognized in Brazil due to underreporting and insufficient data.
DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer
Authors: Qi Zou, Xiaolin Wang, Donglin Ren, Bang Hu, Guannan Tang, Yu Zhang, Meijin Huang, Rish K Pai, Daniel D Buchanan, Aung Ko Win, Polly A Newcomb, William M Grady, Huichuan Yu, Yanxin Luo
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). Methods A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Results Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. Conclusions This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.
Improving lung cancer screening in community oncology programs.
Authors: Linda Sutton, Heather J Sperling
Journal: Journal of Clinical Oncology (2021)

197 Background: Lung Cancer Screening provides a mechanism to detect lung cancers at stages more amendable to curative resection. Nonetheless, data suggests Low Dose Computed Tomography (LDCT) is underutilized as a screening tool; preventing medically eligible patients from diagnosis at earlier stages; leading to reduced treatment options and, ultimately, decreased survival. The Duke Cancer Network (DCN) consists of 12 affiliated cancer programs in 5 states. As several affiliates shared a common goal of improving the uptake of LDCT screening in the community, the DCN created a platform for process improvement in LDCT screening, individualized for participating sites. Methods: DCN-developed surveys for patients and providers explored attitudes toward LDCT screening, and identified targetable access issues and barriers to LDCT screening at DCN-affiliated community cancer centers (aCCC). Armed with the survey data, five aCCC self-selected to work with an experienced Quality/Process Improvement coach to develop individualized projects focusing on one or more aspects of the LDCT screening process. The Q/PI coaches utilized Bite-Size-QI software to facilitate the project and train participants in the QI/PI process. Results: Information from 312 patient and 28 of 50 surveyed providers identified numerous targetable LDCT screening barriers: lack of knowledge about and educational materials to address the benefits of LDCT and tools/analytics to track patients following LDCT screening. Additional, more systematic, barriers identified included: lack of consistent national guidelines for screening, variable insurance coverage and limited availability of smoking cessation programs. Five aCCC self-selected to create individualized process improvement activities were matched to experienced Q/PI coaches. Four sites completed the yearlong project. Three of the aCCC were able to realize improvement in LDCT screening rates with 38%, 27% and 8% increase in rates, respectively, despite overlap with COVID-19 driven shutdowns. Conclusions: An assessment of current state linked to formal Q/PI activities improved uptake of LDCT screening in the majority of participating community cancer programs despite limited resources. Geographically variable COVID-19 required closures did compromise the outcomes. The process led to creation of a number of tools and process improvements to increase awareness of LDCT screening through education and foster collaboration among providers with streamlined referral processes and improved mechanisms of tracking patients. Funding: Provided by AstraZeneca in collaboration with the Duke Cancer Network. Keywords: lung cancer, screening, community, oncology, improvement process, barriers.
P04.22 Tumor treating fields in high-grade glioma patients: A retrospective single-center study
Authors: R Lucaciu, B Suchorska, M Wettig, S Jung, M Scholz
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Tumor-treating fields (TTFields) are a modern anti-mitotic, non-invasive therapy for the treatment of patients with recurrent and newly diagnosed glioblastoma multiforme (GBM). In Europe, Optune® recieved in 2015 the CE certification. TTFields are a low-intensity (1–3 V/cm) approved therapeutic modality using a non-invasive application of intermediate frequency (200 kHz) alternating electric fields through four transducer arrays directly applied to the skin. The EF-14 study has shown that the addition of TTFields to temozolomide chemotherapy in patients with newly diagnosed GBM significantly improved overall survival (OS) and progression-free survival (PFS) without additional adverse events, apart from mild to moderate skin irritations (Stupp et al., JAMA 2017). MATERIAL We retrospectively analyzed data from TTFields-treated patients (2015–2020) that were treated at our department. Patient characteristics such as MGMT promoter methylation status, age, and diagnosis, as well as treatment duration and TTFields therapy usage, were evaluated for this study. RESULTS 29 patients were treated with TTFields therapy between 2015 and 2020 at our hospital. Most patients received TTFields as primary treatment together with temozolomide maintenance therapy. In detail, 48% of patients were diagnosed with newly diagnosed GBM, 41% received TTFields therapy after tumor recurrence and 10% were diagnosed with other high-grade gliomas. In summary, patients could integrate TTFields therapy into their daily life and showed high adherence to the therapy.Particularly, one of our patients (with MGMT-promoter methylation positive) receives TTFields therapy now for almost 1229 days (approx. 41 months) and is still on therapy. Additionally, this patient shows a high usage rate of 86% indicating well integration of the therapy into daily life. CONCLUSION Taken together, our data provided the outcomes of using TTFields together with chemotherapy in the treatment of recurrent and newly diagnosed GBM in our department. Therapy with TTFields has been showing to provide significant clinical benefit for GBM patients.
Multiple oral erosions and ulcers in a patient with malignant melanoma
Authors: Hsi Yen, John Wen-Cheng Chang, Wen-Hung Chung, Chun-Bing Chen
Journal: BMJ (2021)

A man in his 70s presented with a 3 week history of multiple painful, bleeding oral erosions and ulcers. He was receiving immunotherapy (with a phase I trial programmed cell death ligand 1 [PD-L1] inhibitor) for metastatic malignant melanoma. He had received systemic intravenous methylprednisolone to manage a skin eruption for one week before the onset of oral lesions, which were thought to be immunotherapy related. Examination showed numerous, well defined erosions and ulcers with raised, irregular pseudomembranous borders and outer erythematous rings on the lower lip, oral commissures, dorsal tongue, and buccal mucosa (fig 1).



Fig 1 
Numerous well defined ulcers with raised, irregular pseudomembranous borders and outer erythematous …
Stem Cell Microarrays for Assessing Growth Factor Signaling in Engineered Glycan Microenvironments
Authors: Austen L. Michalak, Greg W. Trieger, Kelsey A. Trieger, Kamil Godula
Journal: Advanced Healthcare Materials (2021)

Abstract Extracellular glycans, such as glycosaminoglycans (GAGs), provide an essential regulatory component during the development and maintenance of tissues. GAGs, which harbor binding sites for a range of growth factors (GFs) and other morphogens, help establish gradients of these molecules in the extracellular matrix (ECM) and promote the formation of active signaling complexes when presented at the cell surface. As such, GAGs have been pursued as biologically active components for the development of biomaterials for cell‐based regenerative therapies. However, their structural complexity and compositional heterogeneity make establishing structure‐function relationships for this class of glycans difficult. Here, a stem cell array platform is described, in which chemically modified heparan sulfate (HS) GAG polysaccharides are conjugated to a gelatin matrix and introduced into a polyacrylamide hydrogel network. This array allowed for direct analysis of HS contributions to the signaling via the FGF2‐dependent mitogen activated protein kinase (MAPK) pathway in mouse embryonic stem cells. With the recent emergence of powerful synthetic and recombinant technologies to produce well‐defined GAG structures, a platform for analyzing both growth factor binding and signaling in response to the presence of these biomolecules will provide a powerful tool for integrating glycans into biomaterials to advance their biological properties and applications.
Importance of Family History of Colorectal Carcinoma In Situ Versus Invasive Colorectal Cancer: A Nationwide Cohort Study
Authors: Yu Tian, Elham Kharazmi, Hermann Brenner, Xing Xu, Kristina Sundquist, Jan Sundquist, Mahdi Fallah
Journal: Journal of the National Comprehensive Cancer Network (2021)

The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature.We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS.The lifetime (0-79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5-1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6-1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1-3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3-2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person.Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.
SAR442085, a novel anti-CD38 antibody with enhanced antitumor activity against multiple myeloma
Authors: Sahar Kassem, Béré K. Diallo, Nizar El-Murr, Nadège Carrié, Alexandre Tang, Alain Fournier, Hélène Bonnevaux, Céline Nicolazzi, Marine Cuisinier, Isabelle Arnould, Sukhvinder S. Sidhu, Jill Corre, Hervé Avet-Loiseau, Jean-Luc Teillaud, Helgi van de Velde, Dmitri Wiederschain, Marielle Chiron, Ludovic Martinet, Angela Virone-Oddos
Journal: Blood (2022)

Abstract Anti-CD38 monoclonal antibodies (mAbs) represent a breakthrough in the treatment of multiple myeloma (MM), yet some patients fail to respond or progress quickly with this therapy, highlighting the need for novel approaches. In this study we compared the preclinical efficacy of SAR442085, a next-generation anti-CD38 mAb with enhanced affinity for activating Fcγ receptors (FcγR), with first-generation anti-CD38 mAb daratumumab and isatuximab. In surface plasmon resonance and cellular binding assays, we found that SAR442085 had higher binding affinity than daratumumab and isatuximab for FcγRIIa (CD32a) and FcγRIIIa (CD16a). SAR442085 also exhibited better in vitro antibody-dependent cellular cytotoxicity (ADCC) against a panel of MM cells expressing variable CD38 receptor densities including MM patients’ primary plasma cells. The enhanced ADCC of SAR442085 was confirmed using NK-92 cells bearing low and high affinity FcγRIIIa (CD16a)-158F/V variants. Using MM patients’ primary bone marrow cells, we confirmed that SAR442085 had an increased ability to engage FcγRIIIa, resulting in higher natural killer (NK) cell activation and degranulation against primary plasma cells than preexisting Fc wild-type anti-CD38 mAbs. Finally, using huFcgR transgenic mice that express human Fcγ receptors under the control of their human regulatory elements, we demonstrated that SAR442085 had higher NK cell-dependent in vivo antitumor efficacy and better survival than daratumumab and isatuximab against EL4 thymoma or VK*MYC myeloma cells overexpressing human CD38. These results highlight the preclinical efficacy of SAR442085 and support the current evaluation of this next-generation anti-CD38 antibody in phase I clinical development in patients with relapsed/refractory MM.