tbuckley/cabot-search huggingface dataset:
Comparison of Tightly Controlled Dose Reduction of Biologics With Usual Care for Patients With Psoriasis
Authors: Selma Atalay, Juul M. P. A. van den Reek, Alfons A. den Broeder, Lieke J. van Vugt, Marisol E. Otero, Marcellus D. Njoo, Johannes M. Mommers, Paul M. Ossenkoppele, Marjolein I. Koetsier, Maartje A. Berends, Peter C. M. van de Kerkhof, Hans M. M. Groenewoud, Wietske Kievit, Elke M. G. J. de Jong
Journal: JAMA Dermatology (2020)

Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible.To investigate whether dose reduction (DR) of biologics in patients with stable psoriasis is noninferior to usual care (UC).This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied.Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose.The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index [DLQI] and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for ≥3 months), and proportion of patients with successful dose tapering.Of 120 patients (mean [SD] age, 54.0 [13.2] years; 82 [68%] male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range [IQR], 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred.In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues.ClinicalTrials.gov Identifier: NCT02602925.
Neonatal Mortality After Interhospital Transfer of Pregnant Women for Imminent Very Preterm Birth in Illinois
Authors: Kshama P. Shah, Raye-Ann O. deRegnier, William A. Grobman, Amanda C. Bennett
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Reducing neonatal mortality is a national health care priority. Understanding the association between neonatal mortality and antenatal transfer of pregnant women to a level III perinatal hospital for delivery of infants who are very preterm (VPT) may help identify opportunities for improvement. <h3>Objective</h3> To assess whether antenatal transfer to a level III hospital is associated with neonatal mortality in infants who are VPT. <h3>Design, Setting, and Participants</h3> This population-based cross-sectional study included infants who were born VPT to Illinois residents in Illinois perinatal-network hospitals between January 1, 2015, and December 31, 2016, and followed up for 28 days after birth. Data analysis was conducted from June 2017 to September 2018. <h3>Exposures</h3> Delivery of an infant who was VPT at a (1) level III hospital after maternal presentation at that hospital (reference group), (2) a level III hospital after antenatal (in utero) transfer from another hospital, or (3) a non–level III hospital. <h3>Main Outcomes and Measures</h3> Neonatal mortality. <h3>Results</h3> The study included 4817 infants who were VPT (gestational age, 22-31 completed weeks) and were born to Illinois residents in 2015 and 2016. Of those, 3302 infants (68.5%) were born at a level III hospital after maternal presentation at that hospital, 677 (14.1%) were born at a level III hospital after antenatal transfer, and 838 (17.4%) were born at a non–level III hospital. Neonatal mortality for all infants who were VPT included in this study was 573 of 4817 infants (11.9%). The neonatal mortality was 10.7% for the reference group (362 of 3302 infants), 9.8% for the antenatal transfer group (66 of 677 infants), and 17.3% for the non–level III birth group (145 of 838 infants). When adjusted for significant social and medical characteristics, infants born VPT at a level III hospital after antenatal transfer from another facility had a similar risk of neonatal mortality as infants born at a level III hospital (odds ratio, 0.79 [95% CI, 0.56-1.13]) after maternal presentation at the same hospital. Infants born at a non–level III hospital had an increased risk of neonatal mortality compared with infants born at a level III hospital after maternal presentation to the same hospital (odds ratio, 1.52 [95% CI, 1.14-2.02]). <h3>Conclusions and Relevance</h3> The risk of neonatal mortality was similar for infants who were VPT, whether women initially presented at a level III hospital or were transferred to a level III hospital before delivery. This suggests that the increased risk of mortality associated with delivery at a non–level III hospital may be mitigated by optimizing opportunities for early maternal transfer to a level III hospital.
Urelumab alone or in combination with rituximab in patients with relapsed or refractory B‐cell lymphoma
Authors: John Timmerman, Charles Herbaux, Vincent Ribrag, Andrew D. Zelenetz, Roch Houot, Sattva S. Neelapu, Theodore Logan, Izidore S. Lossos, Walter Urba, Gilles Salles, Radhakrishnan Ramchandren, Caron Jacobson, John Godwin, Cecilia Carpio, Deanne Lathers, Yali Liu, Jaclyn Neely, Satyendra Suryawanshi, Yoshinobu Koguchi, Ronald Levy
Journal: American Journal of Hematology (2020)

Urelumab, a fully human, non-ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T-cell and natural killer-cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and other B-cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug-induced liver injury occurred with urelumab 0.3 mg/kg. Treatment-related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B-cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B-cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care.
LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance
Authors: Melyssa S. Roberts, Jennifer M. Sahni, Morgan S. Schrock, Katrina M. Piemonte, Kristen L. Weber-Bonk, Darcie D. Seachrist, Stefanie Avril, Lindsey J. Anstine, Salendra Singh, Steven T. Sizemore, Vinay Varadan, Matthew K. Summers, Ruth A. Keri
Journal: Cancer Research (2020)

Abstract A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of NEK2 was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, in vitro. In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple in vivo models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. Significance: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.
2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease by Wallace<i>et al</i>
Authors: Byung-Woo Yoo, Jason Jungsik Song, Yong-Beom Park, Sang-Won Lee
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the original article by Wallace et al proposing the new classification for IgG4-related disease (IgG4-RD). 1So far, the comprehensive diagnostic criteria for IgG4-RD (the comprehensive criteria) have been widely used, 2 but recently, the 2019 American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria for IgG4-RD have been developed and validated (the 2019 ACR/EULAR criteria).To determine the agreement rate between the comprehensive and the 2019 ACR/EULAR criteria, we applied the 2019 ACR/EULAR criteria to 40 patients with definite IgG4-RD based on the comprehensive criteria and retrospectively reviewed their medical records.Based on the inclusion criteria of the 2019 ACR/EULAR criteria, total points of ≥20 indicated the classification of IgG4-RD.The mean age of the patients was 60.2 years, and 29 patients (72.5%) were men.With respect to the immunostaining items, no points were assigned to five patients for lymph node biopsy, although they exhibited both IgG4+/IgG+ cells ratio of >40% and IgG4+ cells/high power field (HPF) of >10 on immunostaining.Finally, 1 of 40 patients (2.5%) with definite IgG4-RD was not reclassified as having IgG4-RD according to the 2019 ACR/EULAR criteria.The 2019 ACR/EULAR criteria do not approve the results of immunostaining if the disease involves the lymph nodes.We described five patients who received no points with respect to the immunostaining items in the 2019 ACR/EULAR criteria in table 1.Patient 1 exhibited neither information on typical histopathological features of IgG4-RD nor definite evidence of IgG-RD involvement in the chest, pancreas and biliary tree, kidney or retroperitoneum.Thus, patient 1 obtained only 4 points and could not be reclassified as having IgG4-RD despite the increased concentration of serum IgG4 (4 points).Patient 2 exhibited dense lymphocytic infiltrate and storiform fibrosis in the biopsy samples (13 points) and the highest serum IgG4 concentration range (11 points).Patients 3 and 4 exhibited no information on typical histopathological features of IgG4-RD.However, they had the highest serum IgG4 concentration range and definite evidence of IgG-RD involvement in the chest and kidney on a CT scan.Patient 5 exhibited only dense lymphocytic infiltrate in the biopsy sample (4 points) and the highest serum IgG4 concentration range (11 points).In addition, this patient showed abnormalities in one set of glands (6 points) and in the renal pelvic soft tissue (8 points) on a CT scan.In this study, we elucidated that 97.5% of the patients with definite IgG4-RD were also reclassified as having IgG4-RD
Erratum: Corrigendum: YAP antagonizes innate antiviral immunity and is targeted for lysosomal degradation through IKKɛ-mediated phosphorylation
Authors: Shuai Wang, Feng Xie, Feng Chu, Zhengkui Zhang, Bing Yang, Tong Dai, Liang Gao, Lin Wang, Li Ling, Junling Jia, Hans van Dam, Jin Jin, Long Zhang, Fangfang Zhou
Journal: Nature Immunology (2017)
Abstract P3-06-16: Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers
Authors: Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Benny A Kaipparettu
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is one of non-targetable cancers which are still poorly understood for the driver pathways and therapeutic targets. Over the past decade, cancer metabolism researches have a huge advance. Thus, it has enhanced our understanding on metabolic reprogramming in cancer therapy. We have previously shown that metabolic reprogramming to fatty acid β-oxidation (FAO) is a key energy metabolic pathway in TNBC. Moreover, we reported that FAO regulates c-Src, one of the frequently upregulated oncopathways in TNBC via autophosphorylation of Src at Y419. However, single treatment by FAO inhibitor alone cannot effectively control the tumor progression in TNBC because of metabolic reprogramming and flexibility of tumors. Therefore, proper combination therapies with other metabolic targets are necessary. Recently increasing studies demonstrate that anti-diabetic biguanides have attractive anti-cancer effect in various cancer types including breast cancer (BC). However, its significance as an anti-cancer drug is not well established due to parallel metabolic pathways that support tumor growth. Biguanide like metformin is the most widely administered anti-diabetic agent worldwide. Phenformin, a biguanide derivative similar to metformin, has a greater potency than metformin. Like metformin, phenformin also inhibits mitochondrial electron transport chain (ETC) through complex I inhibition. In addition, biguanides lead to the activation of AMPK, which plays a important role in insulin signaling and energy sensing. Importantly, AMPK is an upstream regulator of FAO pathway because it can phosphorylate ACC to activate FAO. Considering the dependency of TNBC to FAO, we evaluated the therapeutic significance of the combination of biguanides (ETC inhibitors) and FAO inhibitors in TNBC progression and metastasis. And we investigated that targeting both ‘arms’ of the pathway can provide more effective and durable responses in TNBC treatments. Our various in vitro and in vivo studies using TNBC cell lines and PDX models suggest that the combination of both inhibitors can provide better therapeutic benefits in TNBCs. This is a rationale and cost-effective metabolic approach to overcome the currently non-targetable TNBCs. Further study toward the clinical effectiveness of this combination may offer better treatment opportunities for TNBC patients. Citation Format: Jun Hyoung Park, Kwang Hwa Jung, Dongya Jia, Benny A Kaipparettu. Synergistic effect of biguanides and fatty acid β-oxidation inhibitor in triple-negative breast cancers [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 P3-06-16.
Overuse of Broad-Spectrum Antibiotics for Pneumonia
Authors: Michael Klompas
Journal: JAMA Internal Medicine (2020)

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Re: Elise De Bleser, Barbara Alicja Jereczek-Fossa, David Pasquier, et al. Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. Eur Urol 2019;76:732–9
Authors: Pirus Ghadjar, Thomas Wiegel
Journal: European Urology (2019)
S851 A FULLY HUMAN BISPECIFIC ANTIBODY FUNCTIONALLY RESCUES FACTOR VIII DEFICIENCY EX VIVO
Authors: W. Wang, J. Blackwood, R. Magliozzi, L. Moraes, A. Sinopoli, B. Chi, C. Sellick, C. Pearce, I. Theurl, J. Hollins, K. Dickson, A. Bradley, E.‐C. Lee
Journal: HemaSphere (2019)

Background: Haemophilia A is caused by deficiency of Factor VIII (F.VIII), an essential blood‐clotting cofactor. Prophylaxis or on‐demand treatment with recombinant FVIII forms the current standard of care to prevent bleeding in Haemophilia A patients in the developed world. However, approximately 30% of severe haemophilia A patients develop inhibitory antibodies against F.VIII. Moreover, FVIII treatment requires venous access which is burdensome. The recent successful clinical trials and subsequent regulatory approval of a F.VIII‐mimetic bispecific antibody, Hemlibra, in Haemophilia A patients with inhibitors have provided much needed hope for suffers and their family. However, whilst Hemilibra represents a major breakthrough in the field, there remain some concerns about balancing the risks of bleeding with those of thrombosis when using this agent. Aims: To develop a new fully human FVIII mimetic bispecific antibody that can support the assembly of a functional Factor IXa (F.IXa) and Factor X (F.X) complex, thereby replacing F.VIII function in vivo . Methods: Using Kymab's bispecific antibody platform, we developed KY1049, a fully human common light chain (CLC) bispecific antibody, to test as an effective functional mimetic of F.VIII. KY1049 bispecific heterodimer was purified using standard Protein A chromatography, followed by cation ion exchange chromatography (cIEX). The mass and heterodimer purity of the bispecific molecule was confirmed using Mass Spectrometry (MS). A combination of in vitro and ex vivo assays was used to characterize the cIEX purified bispecific antibody, including chromogenic FXase and Activated Partial Thromboplastin Time (aPTT). The affinities of the FIX arm and FX arm of KY1049 bispecific to FIX and FX, respectively, were determined using Surface Plasmon Resonance (SPR). Results: cIEX purified KY1049 molecule was confirmed as a single species by MS. After denaturing, the molecular weights of the two heavy chains and one light chain matches in silico predicted molecular weights. Purified KY1049 actively generated activated F.X (F.Xa) and functionally rescued the clotting defect in F.VIII‐depleted plasma in the aPTT assay. Importantly, ex vivo activities of KY1049 indicates its therapeutic benefit is likely to be similar in efficacy to Hemlibra. KY1049 binds F.IX and F.X simultaneously by SPR, but the affinities are different from those reported of Hemlibra. Summary/Conclusion: We have developed KY1049, a FVIII mimetic bispecific antibody, that demonstrates biological activities comparable to those reported for Hemlibra. Its therapeutic benefit is likely to be at least as effective as Hemlibra. Furthermore, initial analysis of the KY1049 molecule also showed some differences between the two molecules which could be harnessed to enhance its physical properties and activity.
The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future
Authors: Heike J. Wobst, Korrie L. Mack, Dean G. Brown, Nicholas J. Brandon, James Shorter
Journal: Medicinal Research Reviews (2020)

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive loss of muscle function. It is the most common adult‐onset form of motor neuron disease, affecting about 16 000 people in the United States alone. The average survival is about 3 years. Only two interventional drugs, the antiglutamatergic small‐molecule riluzole and the more recent antioxidant edaravone, have been approved for the treatment of ALS to date. Therapeutic strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 different drugs have been tested in the clinic to date. Here, we summarize and classify interventional therapeutic strategies based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in ALS and highlight emerging preclinical strategies that could provide a breakthrough in the battle against this relentless disease.