tbuckley/cabot-search huggingface dataset:
Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing
Authors: E. Del Duca, J. Ruano Ruiz, A.B. Pavel, R.D. Sanyal, T. Song, J. Gay‐Mimbrera, N. Zhang, Y.D. Estrada, X. Peng, Y. Renert‐Yuval, R.G. Phelps, R. Paus, J.G. Krueger, E. Guttman‐Yassky
Journal: British Journal of Dermatology (2020)

Frontal fibrosing alopecia (FFA) is a scarring alopecia with unclear pathogenesis and a progressive course. The disease has a major impact on patients' quality of life and there is a lack of effective treatment to halt disease progression.We profiled lesional and nonlesional scalp biopsies collected in 2017 from patients with FFA (n = 12) compared with scalp biopsies from patients with alopecia areata (AA) (n = 8) and controls (n = 8) to evaluate gene and protein expression, including the primary outcome (CXCL9). We determined significant differences between biomarkers using a two-sided Student's t-test adjusting P-values by false discovery rate.Significant increases were seen in CD8+ cytotoxic T cells, CD11c+ dendritic cells, CD103+ and CD69+ tissue-resident memory T cells in FFA and AA vs. control scalp (P < 0·05), with corresponding significantly upregulated granzyme B mRNA, particularly in FFA (P < 0·01). In AA, cellular infiltrates were primarily concentrated at the bulb, while in FFA these were mainly localized at the bulge. FFA demonstrated significant upregulation of T helper 1/intereferon (IFN) (IFN-γ, CXCL9/CXCL10), the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway (STAT1, JAK3) and fibrosis-related products (vimentin, fibronectin; P < 0·05), with no concomitant downregulation of hair keratins and the T-regulatory marker, forkhead box P3, which were decreased in AA. The stem cell markers CD200 and K15 demonstrated significantly reduced expression only in FFA (P < 0·05).These data suggest that follicular damage and loss of stem cells in FFA may be mediated through immune attack in the bulge region, with secondary fibrosis and reduced but still detectable stem cells. JAK/STAT-targeting treatments may be able to prevent permanent follicular destruction and fibrosis in early disease stages.
HER2-Mediated Internalization of Cytotoxic Agents in<i>ERBB2</i>Amplified or Mutant Lung Cancers
Authors: Bob T. Li, Flavia Michelini, Sandra Misale, Emiliano Cocco, Laura Baldino, Yanyan Cai, Sophie Shifman, Hai-Yan Tu, Mackenzie L. Myers, Chongrui Xu, Marissa Mattar, Inna Khodos, Megan Little, Besnik Qeriqi, Gregory Weitsman, Clare J. Wilhem, Alshad S. Lalani, Irmina Diala, Rachel A. Freedman, Nancy U. Lin, David B. Solit, Michael F. Berger, Paul R. Barber, Tony Ng, Michael Offin, James M. Isbell, David R. Jones, Helena A. Yu, Sheeno Thyparambil, Wei-Li Liao, Anuja Bhalkikar, Fabiola Cecchi, David M. Hyman, Jason S. Lewis, Darren J. Buonocore, Alan L. Ho, Vicky Makker, Jorge S. Reis-Filho, Pedram Razavi, Maria E. Arcila, Mark G. Kris, John T. Poirier, Ronglai Shen, Junji Tsurutani, Gary A. Ulaner, Elisa de Stanchina, Neal Rosen, Charles M. Rudin, Maurizio Scaltriti
Journal: Cancer Discovery (2020)

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627.
Covid-19: medical students and FY1 doctors to be given early registration to help combat covid-19
Authors: Anna Harvey
Journal: BMJ (2020)

<h3>Objectives</h3> To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). <h3>Methods</h3> Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. <h3>Results</h3> Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p&lt;0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12–8.85) for controls and 6.90 (6.45–7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. <h3>Conclusions</h3> Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology
Authors: Brian Owens
Journal: The Lancet Rheumatology (2020)

Excitement about a potential new treatment for the coronavirus disease 2019 (COVID-19) pandemic currently engulfing the world is causing problems for patients with arthritis and systemic lupus erythematosus (SLE), who routinely use the drug to control their symptoms.
Targeted tumour theranostics in mice via carbon quantum dots structurally mimicking large amino acids
Authors: Shuhua Li, Wen Su, Hao Wu, Ting Yuan, Chang Yuan, Jun Liu, Gang Deng, Xingchun Gao, Zeming Chen, Youmei Bao, Fanglong Yuan, Shixin Zhou, Hongwei Tan, Yunchao Li, Xiaohong Li, Louzhen Fan, Jia Zhu, Ann T. Chen, Fuyao Liu, Yu Zhou, Miao Li, Xingchen Zhai, Jiangbing Zhou
Journal: Nature Biomedical Engineering (2020)
Mediastinal Epithelioid Hemangioendothelioma Revealed on 68Ga-DOTATATE PET/CT
Authors: Yu Long, Fuqiang Shao, Xiaoli Lan
Journal: Clinical Nuclear Medicine (2020)

Abstract Epithelioid hemangioendothelioma is a rare vascular sarcoma, and it rarely leads abnormal serum calcium. Here we presented a 61-year-old woman with suspected tumor-induced osteomalacia who underwent 68 Ga-DOTATATE PET/CT to detect possible culprit tumor. The images showed a hypermetabolic paraspinal soft nodule in the right upper posterior mediastinum, which suggested a somatostatin receptor–positive tumor. The tumor was resected and pathologically confirmed as epithelioid hemangioendothelioma.
Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives
Authors: Yizhen Yin, Fener Chen
Journal: Acta Pharmaceutica Sinica B (2020)

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.
Abstract P3-11-26: Investigating the synergistic anti-cancer effects on mitochondrial function in breast cancer cells using arctigenin, cinnamaldehyde, and chlorogenic acid individually and in combination
Authors: Caroline Schuster, Lauren S Gollahon
Journal: Cancer Research (2020)

Abstract One of the major obstacles in current breast cancer treatment efficacy is the ability of breast cancer cells to develop resistance to chemotherapeutic drugs. In addition, a second major obstacle is the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. Many of these current chemotherapeutics target DNA (repair, replication, division). As a result, the bystander effect to normal cells and tissues is significant. However, one major difference between cancer and normal cells is their metabolism. The Warburg Effect suggests that cancer cells prefer a glycolytic, hypoxic environment. Emerging studies have begun to delineate differences in mitochondrial function between cancer and normal cells. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on application of natural product components. Previous studies from our lab demonstrated the efficacy of a mixture of plant extracts in killing cancer cells. Proteomics studies showed significant mitochondrial disruption in the cancer cells compared to normal cells. Here, we investigate three of the main components, identified by Mass Spectometry, to determine their anticancer properties compared to the whole extracts’ mixture. Arctigenin, chlorogenic acid, and cinnamaldehyde all demonstrate anti-cancer activity. We hypothesize that each component of the whole extract causes breast cancer cell death by disruption of mitochondrial activity and metabolic shifts, and lead to an increase in oxidative stress that is further amplified by combination treatment. These small molecules were administered to MDA-MB-231 and MCF-7 breast cancer or normal MCF-10A and MCF-12F breast cells, either alone or in combination. To evaluate differences in cell response, mitochondrial integrity and metabolic shifts were evaluated by flow cytometry, fluorescence microscopy and the Agilent Seahorse XF Cell Mito Stress Test. The ladder measures the mitochondria’s oxygen consumption rate, basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration. This study provides evidence that targeting the mitochondria may be a more effective anticancer treatment and that either components of natural products or combinations thereof offer new approaches in treating breast cancer that significantly reduce off-target effects to normal cells. Citation Format: Caroline Schuster, Lauren S Gollahon. Investigating the synergistic anti-cancer effects on mitochondrial function in breast cancer cells using arctigenin, cinnamaldehyde, and chlorogenic acid individually and in combination [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-26.
Therapeutic Results in Patients with Hodgkin's Lymphoma Treated with Brentuximab Vedotin — Bulgarian Experience
Authors: Veselina S Goranova Marinova, Kalina Ignatova, Penka Ganeva, Emil Spasov, Ilina Micheva, Atanas Radinov, Raya Petrova, Gergana Tzvetkova, Eugueni Hadzhiev, Stefan E Goranov, Liana Gercheva
Journal: Blood (2017)
Out-of-clinic measurement of sweat chloride using a wearable sensor during low-intensity exercise
Authors: Dong-Hoon Choi, Grant B. Kitchen, Mark T. Jennings, Garry R. Cutting, Peter C. Searson
Journal: npj Digital Medicine (2020)

Wearable sensors have the potential to enable measurement of sweat chloride outside the clinic. Here we assess the feasibility of mild exercise as an alternative to pilocarpine iontophoresis for sweat generation. The results from this proof-of-concept study suggest that mild exercise could be a feasible approach to obtain reliable measurements of sweat chloride concentration within 20-30 min using a wearable sensor.
Cancer guidelines during the COVID-19 pandemic
Authors: Talha Khan Burki
Journal: The Lancet Oncology (2020)

As of April 1, 2020, more than 800 000 cases of coronavirus disease 2019 (COVID-19) had been confirmed worldwide. The death toll in Italy is approaching 12 000 people, with Spain not far behind. The USA has reported more than 164 000 cases of the disease, including more than 38 000 cases in New York City alone. There are concerns that the COVID-19 could overwhelm health-care systems worldwide. Many nations have reported a shortage of ventilators.
Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery
Authors: C. Marc Samama, Silvy Laporte, Nadia Rosencher, Philippe Girard, Juan Llau, Patrick Mouret, William Fisher, Javier Martínez-Martín, Daniel Duverger, Béatrice Deygas, Emilie Presles, Michel Cucherat, Patrick Mismetti
Journal: New England Journal of Medicine (2020)

Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients.
Safety and immunogenicity of the tetravalent, live-attenuated dengue vaccine Butantan-DV in adults in Brazil: a two-step, double-blind, randomised placebo-controlled phase 2 trial
Authors: Esper G Kallas, Alexander Roberto Precioso, Ricardo Palacios, Beatriz Thomé, Patrícia Emília Braga, Tazio Vanni, Lúcia M A Campos, Lilian Ferrari, Gabriella Mondini, Maria da Graça Salomão, Anderson da Silva, Heloisa M Espinola, Joane do Prado Santos, Cecilia L S Santos, Maria do Carmo S T Timenetsky, João Luiz Miraglia, Neuza M F Gallina, Daniela Weiskopf, Alessandro Sette, Raphaella Goulart, Rafael Tavares Salles, Alvino Maestri, Adriana Maluf Elias Sallum, Sylvia Costa Lima Farhat, Neusa K Sakita, Juliana C O A Ferreira, Cassia G T Silveira, Priscilla R Costa, Isaias Raw, Stephen S Whitehead, Anna P Durbin, Jorge Kalil
Journal: The Lancet Infectious Diseases (2020)
Abstract ES11-2: Neoadjuvant Systemic Treatment (NST): Tailoring Response by Sub-type
Authors: JC Chang
Journal: Cancer Research (2020)

Abstract Achieving a pathologic complete response (pCR) after neoadjuvant systemic treatment (NST) is clearly associated with improved survival in breast cancer patients, especially with HER2 and triple negative subtypes. In HER2-positive breast cancer patients, the neoadjuvant platform has allowed for the unprecedented accelerated approval for pertuzumab based on improved pCR rates. The KATHERINE trial, in patients who did not achieve pCR following standard trastuzumab/pertuzumab/chemotherapy, demonstrated for the first time that switching to trastuzumab-emtansine (TDM1) led to significant benefit, creating an interesting research paradigm for these high-risk patients with residual disease. For patients with residual disease, the CREATE-X trial demonstrated survival improvement with capecitabine, especially in patients with triple negative disease. New promising agents in the metastatic setting that are being incorporated into NST include immune-check-point inhibitors and cyclin-dependent kinase inhibitors. Evolving technologies like next generation sequencing and gene expression profiles have improved our knowledge regarding the biology of residual disease, and the mechanisms behind treatment resistance, and potentially, metastases. NST allows for testing of new promising treatment regimens - both escalation and de-escalation - depending on sub-types, before surgery. The management and strategies post-NST and the management of residual disease will be discussed. Citation Format: JC Chang. Neoadjuvant Systemic Treatment (NST): Tailoring Response by Sub-type [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES11-2.
Evaluation of polymyxin B in combination with 13 other antibiotics against carbapenemase-producing Klebsiella pneumoniae in time-lapse microscopy and time-kill experiments
Authors: P. Wistrand-Yuen, A. Olsson, K.-P. Skarp, L.E. Friberg, E.I. Nielsen, P. Lagerbäck, T. Tängdén
Journal: Clinical Microbiology and Infection (2020)

ObjectivesThis study aimed to explore the interactions of polymyxin B in combination with 13 other antibiotics against carbapenemase-producing Klebsiella pneumoniae.MethodsFive clinical isolates of multidrug-resistant K. pneumoniae producing KPC-2, KPC-3, NDM-1, OXA-48 and VIM-1 carbapenemases were used. Polymyxin B was tested alone and in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampicin, temocillin, thiamphenicol and trimethoprim. Inhibition of growth during antibiotic exposure was evaluated in 24-hr automated time-lapse microscopy experiments. Combinations that showed positive interactions were subsequently evaluated in static time-kill experiments.ResultsAll strains carried multiple (≥9) resistance genes as determined by whole-genome sequencing. In the initial screening the combination of polymyxin B and minocycline was most active with enhanced activity compared with the single antibiotics detected against all strains. Positive interactions were also observed with polymyxin B in combination with rifampicin and fosfomycin against four of five strains and less frequently with other antibiotics. Time-kill experiments demonstrated an additive or synergistic activity (1–2 log10 or ≥2 log10 CFU/mL reduction, respectively, compared with the most potent single antibiotic) with 21 of 23 tested combinations. However, because of regrowth, only 13 combinations were synergistic at 24 hr. Combinations with minocycline or rifampicin were most active, each showing synergy and bacteriostatic or bactericidal effects resulting in 1.93–3.97 and 2.55–5.91 log10 CFU/mL reductions, respectively, after 24 hr against four strains.DiscussionPolymyxin B in combination with minocycline, rifampicin or fosfomycin could be of potential clinical interest. Time-lapse microscopy showed some discrepancy in results compared with the time-kill data but was useful for screening purposes.
Abstract P3-08-66: Metaplastic breast cancer in patients older than 65 years
Authors: Johnny Chahine, Bicky Thapa, Xuefei Jia, Abdo Haddad
Journal: Cancer Research (2020)

Abstract Background: Metaplastic breast cancer (MBC) is a rare histologic subtype of breast cancer. It comprises less than 1% of all breast cancers. We evaluated the clinical characteristics and outcomes of MBC in geriatric patients older than age 65. Methods: We reviewed the chart of the pathologically proven MBC cases from 2000-2017. Only patients with age more than 65 years were included in the study for analysis. Results: A total of 48 MBC patients were included in the study. Thirty-six (76%) were white and 11 (23%) black. The number of patients in stages I, II, III, and IV were 12, 26, 6, and 4, respectively; 39 (81%) had nuclear grade III. Three (6%) had progesterone receptor positive, 3 (6%) were Her2 positive, and 4 (10%) were estrogen receptor positive. The most common distant metastases were lung (20%), followed by bone (12%). Fifty percent had a lumpectomy, 11% had hormonal therapy, and 60% had radiation therapy. Only 50% of patients received chemotherapy, out of which 46% received anthracycline. On univariable analysis, stage of the MBC and metastasis to the lung, bone, and brain were associated with worse overall survival (OS). There was no statistical significance in OS when stage II was compared with stage I MBC. Stage III had median OS of 18 months with HR of 3.25 (95% CI 0.85, 12.44) (p=0.086) and stage IV had 10 months median OS with HR of 11.17, (95% CI 2.37, 52.62) (p=0.002). Hormonal therapy, radiation therapy, and type of chemotherapy (anthracycline vs. non-anthracycline) did not show any statistical significance in regards to OS and progression-free survival. Conclusion: In our study, MBC demonstrated overall poor survival and progression-free survival. Only stage of the MBC and metastasis to brain bone and lung proved to predict worse survival. Citation Format: Johnny Chahine, Bicky Thapa, Xuefei Jia, Abdo Haddad. Metaplastic breast cancer in patients older than 65 years [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-66.
Simultaneous ipsilateral DSM-TACE and PVE as a possible new gold standard strategy for preoperative augmentation of future liver remnant in patients with solid liver malignancies
Authors: Oleg Kotenko, Oleksander Korshak, Oleksii Popov, Oleksander Grinenko, Denis Fedorov, Andrii Husiev, Oleksander Ostapishen, Marat Grigorjan, Andrii Zhylenko, Nellya Ablaeva, Vladislav Kropelnytskyi, Vadim Kondratiuk, Tetiana Terzova, Maria Stassiuk
Journal: International Journal of Surgery (2020)