tbuckley/cabot-search huggingface dataset:
First-in-human HER2-targeted Bispecific Antibody KN026 for the Treatment of Patients with HER2-positive Metastatic Breast Cancer: Results from a Phase I Study
Authors: Jian Zhang, Dongmei Ji, Li Cai, Herui Yao, Min Yan, Xiaojia Wang, Weina Shen, Yiqun Du, Hui Pang, Xiuping Lai, Huiai Zeng, Jian Huang, Yan Sun, Xinxin Peng, Junfang Xu, Jing Yang, Fei Yang, Ting Xu, Xichun Hu
Journal: Clinical Cancer Research (2021)

KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This first-in-human phase I study evaluated the safety/tolerability, pharmacokinetics, preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to patients with HER2-positive metastatic breast cancer (MBC).Female patients with HER2-positive MBC who had progressed on prior anti HER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (once weekly), 10 mg/kg (once weekly), 20 mg/kg (once every 2 weeks), or 30 mg/kg (once every 3 weeks). Dose escalation was guided by a "3+3" dose escalation rule followed by dose expansion.Sixty-three patients were enrolled. The most common treatment-related adverse events (TRAE) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). Only 4 patients reported grade 3 TRAEs. Results from exposure-response analysis supported the selection of the recommended phase II doses at 20 mg/kg once every 2 weeks or 30 mg/kg once every 3 weeks, which had objective response rates (ORR) of 28.1% and median progression-free survival (PFS) of 6.8 months (95% confidence interval: 4.2-8.3) in 57 patients. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no co-amplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and median PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively).KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.
Sound sleep: Lullabies as a test case for the neurobiological effects of music—CORRIGENDUM
Authors: Miriam Akkermann, Ugur Can Akkaya, Cagatay Demirel, Dirk Pflüger, Martin Dresler
Journal: Behavioral and Brain Sciences (2021)

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A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
Authors: Sherise C. Rogers, Ji-Hyun Lee, Brian Hemendra Ramnaraign, Kathryn Hitchcock, Steven J. Hughes, Anita Ahmed Turk, Karen Bullock Russell, Ahmad El-Far, Ryan M. Thomas, Jesus C. Fabregas, Ilyas Sahin, Carmen Joseph Allegra, David L. DeRemer, Thomas J. George
Journal: Journal of Clinical Oncology (2022)

TPS619 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) in combination with 5FU/LV is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Exploratory ctDNA and stool microbiome analyses are also planned. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
Phosphate dysregulation via the XPR1–KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer
Authors: Daniel P. Bondeson, Brenton R. Paolella, Adhana Asfaw, Michael V. Rothberg, Thomas A. Skipper, Carly Langan, Gabriel Mesa, Alfredo Gonzalez, Lauren E. Surface, Kentaro Ito, Mariya Kazachkova, William N. Colgan, Allison Warren, Joshua M. Dempster, John M. Krill-Burger, Maria Ericsson, Andrew A. Tang, Iris Fung, Emily S. Chambers, Mai Abdusamad, Nancy Dumont, John G. Doench, Federica Piccioni, David E. Root, Jesse Boehm, William C. Hahn, Michael Mannstadt, James M. McFarland, Francisca Vazquez, Todd R. Golub
Journal: Nature Cancer (2022)
22P EMB-01: An EGFR-cMET bispecific antibody, in advanced/metastatic solid tumors phase I results
Authors: Z. Qing, N. Gabrail, D. Uprety, J. Rotow, B. Han, P.A. Jänne, M. Nagasaka, M. Zheng, Y. Zhang, G. Yang, Y. Sun, B. Peng, Y-L. Wu
Journal: Annals of Oncology (2022)
Cover Image, Volume 42, Issue 4
Authors: Chanju Lee, Hyunji Lee, Hayoon Cho, Soyoung Kim, Ilseob Choi, Young‐Sik Hwang, Hyunju Jeong, Hogi Jang, Sehyun Pak, Deok‐Sang Hwang, Ik‐Hwan Han, Hyunsu Bae
Journal: Cancer Communications (2022)

The cover image is based on the Letter to Editor Combination of anti-PD-L1 antibody with peptide MELdKLA targeting M2 tumor-associated macrophages suppresses breast cancer metastasis by Hyun-Soo Bae et al., https://doi.org/10.1002/cac2.12276.
Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas
Authors: Jennifer Y. Wo, Jeffrey W. Clark, Christine E. Eyler, Mari Mino-Kenudson, Samuel J. Klempner, Jill N. Allen, Florence K. Keane, Aparna R. Parikh, Eric Roeland, Lorraine C. Drapek, David P. Ryan, Ryan B. Corcoran, Emily Van Seventer, Isobel J. Fetter, Heather A. Shahzade, Melin J. Khandekar, Michael Lanuti, Christopher R. Morse, Rebecca S. Heist, Christine A. Ulysse, Benjamin Christopher, Christian Baglini, Beow Y. Yeap, John T. Mullen, Theodore S. Hong
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We performed a NCI-sponsored, prospective study of neoadjuvant FOLFIRINOX followed by chemoradiation with carboplatin/paclitaxel followed by surgery in patients with locally advanced gastric or gastroesophageal cancer. Patients and Methods: The primary objective was to determine completion rate of neoadjuvant FOLFIRINOX × 8 followed by chemoradiation. Secondary endpoints were toxicity and pathologic complete response (pCR) rate. Exploratory analysis was performed of circulating tumor DNA (ctDNA) to treatment response. Results: From October 2017 to June 2018, 25 patients were enrolled. All patients started FOLFIRINOX, 92% completed all eight planned cycles, and 88% completed chemoradiation. Twenty (80%) patients underwent surgical resection, and 7 had a pCR (35% in resected cohort, 28% intention to treat). Tumor-specific mutations were identified in 21 (84%) patients, of whom 4 and 17 patients had undetectable and detectable ctDNA at baseline, respectively. Presence of detectable post-chemoradiation ctDNA (P = 0.004) and/or postoperative ctDNA (P = 0.045) were associated with disease recurrence. Conclusions: Here we show neoadjuvant FOLFIRINOX followed by chemoradiation for locally advanced gastroesophageal cancer is feasible and yields a high rate of pCR. ctDNA appears to be a promising predictor of postoperative recurrence. See related commentary by Catenacci, p. 6281
Statistics or biology: the zero-inflation controversy about scRNA-seq data
Authors: Ruochen Jiang, Tianyi Sun, Dongyuan Song, Jingyi Jessica Li
Journal: Genome biology (2022)

Researchers view vast zeros in single-cell RNA-seq data differently: some regard zeros as biological signals representing no or low gene expression, while others regard zeros as missing data to be corrected. To help address the controversy, here we discuss the sources of biological and non-biological zeros; introduce five mechanisms of adding non-biological zeros in computational benchmarking; evaluate the impacts of non-biological zeros on data analysis; benchmark three input data types: observed counts, imputed counts, and binarized counts; discuss the open questions regarding non-biological zeros; and advocate the importance of transparent analysis.
76TiP RMC-4630 and sotorasib for advanced KRASG12C NSCLC after failure of prior standard therapies: A phase II trial
Authors: M.L. Johnson, R. Langdon, D. Ellison, A. Spira, H. Amin, M. Castine, D.B. Daniel, S. Sohoni, Y-C. Chen, J. Hayes, Y. Mu, S. Masciari, X. Wang, S. Toya
Journal: Annals of Oncology (2022)
Abstract 12146: Acute Nitroglycerin Treatment Improves Exercise Hemodynamics, but Not Ventilation-Perfusion Matching in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Bryce N Balmain, Andrew R Tomlinson, James P Macnamara, Satyam Sarma, Christopher M Hearon, Sheryl A Livingston, Margot Morris, Raksa B Moran, Jessica N Alcala, Marcus Payne, Mitchel Samels, Teverick Boyd, David Lee, Stephanie Baird, Benjamin D Levine, Tony G Babb
Journal: Circulation (2021)

Introduction: Heart failure with preserved ejection fraction (HFpEF) patients exhibit a marked rise in PCWP during exercise, which may contribute to ventilation-perfusion (V/Q) mismatch and manifest as an increase in alveolar dead space (alveolar V D ) and alveolar-arterial PO 2 difference (AaPO 2 ). Nitrates reduce PCWP during exercise in HFpEF, but whether nitrates also reduce V/Q mismatch during exercise is unknown. Hypothesis: The increase in PCWP and V/Q mismatch during exercise would be attenuated with acute nitroglycerin (NTG) treatment compared with placebo in HFpEF patients. Methods: 13 patients performed a 6min cycling test at 20W and an incremental cycling test (with right-heart and arterial catheterization) with placebo and NTG treatment. The physiologic dead space to tidal volume (V D /V T ) was calculated using the Enghoff modification of the Bohr equation. Alveolar V D was calculated as: V D /V T x V T - anatomic dead space (anatomic V D , estimated as 2mL/kg lean body mass). AaPO 2 was calculated using the alveolar gas equation. Data were analyzed using a 2-way ANOVA. Results: PCWP decreased with NTG at 20W (placebo: 21.1±6.2 vs. NTG: 16.5±6.1mmHg, p=0.02) and peak exercise (placebo: 33.7±7.1 vs. NTG: 26.2±5.6mmHg, p&lt;0.01). However, alveolar V D did not differ between treatments at rest (placebo: 0.11±0.07 vs. NTG:0.12±0.06L/breath, p=0.91), 20W (placebo: 0.22±0.09 vs. NTG: 0.24±0.10L/breath, p=0.62), or peak exercise (placebo: 0.34±0.14 vs. NTG:0.36±0.16L/breath, p=0.83). Nor did AaPO 2 differ between treatments at rest (placebo: 17.6±4.3 vs. NTG: 18.3±5.7mmHg, p=0.76), 20W (placebo: 22.0±6.9 vs. NTG: 22.1±8.1mmHg, p=0.99), or peak exercise (placebo: 25.1±9.1 vs. NTG: 27.8±9.9mmHg, p=0.41). No significant exercise-by-treatment interaction was detected for V D /V T (p=0.80). Conclusions: This study showed that NTG attenuated the increase in PCWP, but had no effect on the increase in alveolar V D or AaPO 2 during exercise. These findings suggest that the exercise-induced increase in V/Q mismatch may not be exclusively related to abnormal exercise hemodynamics. Further study is required to determine the clinical consequences and the mechanism(s) responsible for the progressive increase in V/Q mismatch during exercise in HFpEF patients.
Two New Neutrophil Subsets Define a Discriminating Sepsis Signature
Authors: Aïda Meghraoui-Kheddar, Benjamin G. Chousterman, Noëlline Guillou, Sierra M. Barone, Samuel Granjeaud, Helene Vallet, Aurélien Corneau, Karim Guessous, Charles de Roquetaillade, Alexandre Boissonnas, Jonathan M. Irish, Christophe Combadière
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Sepsis is the leading cause of death in adult ICUs. At present, sepsis diagnosis relies on nonspecific clinical features. It could transform clinical care to have immune-cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Objectives: To identify an early, specific immune signature of sepsis severity that does not overlap with other inflammatory biomarkers and that distinguishes patients with sepsis from those with noninfectious inflammatory syndrome. Methods: Mass cytometry combined with computational high-dimensional data analysis was used to measure 42 markers on whole-blood immune cells from patients with sepsis and control subjects and to automatically and comprehensively characterize circulating immune cells, which enables identification of novel, disease-specific cellular signatures. Measurements and Main Results: Unsupervised analysis of high-dimensional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+ immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 (programmed death ligand 1) expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils correlated with clinical severity. Conclusions: This study showed that these two new neutrophil subsets were specific to sepsis and detectable through routine flow cytometry by using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.
Multifunctional co-transport carriers based on cyclodextrin assembly for cancer synergistic therapy
Authors: Shouhui Yi, Rongqiang Liao, Wei Zhao, Yusheng Huang, Yi He
Journal: Theranostics (2022)

In the past few years, drug delivery systems have been used extensively to improve solubility, stability, and pharmacokinetics of chemotherapeutic drugs.However, traditional delivery systems fail to fulfill the required standard of effectiveness, primarily owing to issues of drug resistance exhibited by cancer cells and inherent differences among the patients.In this regard, combination therapy offers advantages of synergistic mechanism, reduced drug dosage, and enhanced therapeutic effect, which can be effectively utilized for the treatment of cancer.However, different types of therapeutic agents exhibit different pharmacokinetic properties and action targets in vivo, which lead to uncontrollable concentration ratio of therapeutic agents at the lesion site.This in turn causes serious side effects and affects synergistic anticancer effect.Importantly, multifunctional co-delivery systems are characterized by good pharmacokinetic properties, ability to provide targeted delivery, and controlled release in response to tumor microenvironment.Such delivery systems are widely used for co-delivery of therapeutic agents, which further assist in obtaining better synergistic anticancer effect, and can be potentially used for clinical application.Multifunctional co-delivery systems often exhibit complex structures and construction process.Since cyclodextrin is characterized by self-assembly property, it is possible to quickly construct cyclodextrin-based multifunctional co-delivery systems, with convenience and flexibility.The application of cyclodextrin in the construction of multifunctional co-delivery systems for cancer therapy has gained immense attention in the past few years.The present study provided overview of latest progress in the field of cyclodextrin-based multifunctional co-delivery systems for cancer synergistic therapy.
Subclinical Hypothyroidism After 225Ac-DOTATATE Therapy in a Case of Metastatic Neuroendocrine Tumor
Authors: Anwin Joseph Kavanal, Swayamjeet Satapathy, Ashwani Sood, Divya Khosla, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2021)

Abstract Radiation-induced thyroid dysfunction is very rarely associated with peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors using β-emitting radionuclides. With the emergence of α radionuclide such as 225 Ac, PRRT using these radionuclides has shown better results; however, data on the toxicity profile are limited. This is a case report describing the thyroid dysfunction developed in a patient with inoperable metastatic neuroendocrine tumor with unknown primary after PRRT using 225 Ac-DOTATATE, which has never been reported previously.
Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial
Authors: Stephen R. Russell, Arlene V. Drack, Artur V. Cideciyan, Samuel G. Jacobson, Bart P. Leroy, Caroline Van Cauwenbergh, Allen C. Ho, Alina V. Dumitrescu, Ian C. Han, Mitchell Martin, Wanda L. Pfeifer, Elliott H. Sohn, Jean Walshire, Alexandra V. Garafalo, Arun K. Krishnan, Christian A. Powers, Alexander Sumaroka, Alejandro J. Roman, Eva Vanhonsebrouck, Eltanara Jones, Fanny Nerinckx, Julie De Zaeytijd, Rob W. J. Collin, Carel Hoyng, Peter Adamson, Michael E. Cheetham, Michael R. Schwartz, Wilhelmina den Hollander, Friedrich Asmus, Gerard Platenburg, David Rodman, Aniz Girach
Journal: Nature Medicine (2022)

Abstract CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A&gt;G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.
Abstract 014: Protein Biomarkers Of Healthy Dietary Patterns In The Atherosclerosis Risk In Communities Study
Authors: Shutong Du, Hyunju Kim, Jingsha Chen, Josef Coresh, Nilanjan Chatterjee, Peter Ganz, Eric Boerwinkle, Bing Yu, Casey M Rebholz
Journal: Circulation (2022)

Introduction: Molecular mechanisms underlying the benefits of healthy dietary patterns on chronic diseases are poorly understood. Identifying protein biomarkers of healthy diets can help us characterize biological pathways influenced by diet quality and confirm the validity of established healthy dietary patterns. Objectives: To identify protein biomarkers that are associated with diet quality using four metrics of adherence to dietary guidelines and healthy dietary patterns: the Alternative Healthy Eating Index-2010 (AHEI-2010); the Alternate Mediterranean Diet (aMED); the Dietary Approaches to Stop Hypertension (DASH) diet; and the Healthy Eating Index-2015 (HEI-2015). Methods: We examined 4,877 plasma proteins among 10,593 participants with available proteomics and dietary data from the Atherosclerosis Risk in Communities (ARIC) Study at visit 3 (1993-1995). Dietary intake data were collected through a food frequency questionnaire, and proteins were measured in plasma using an aptamer-based proteomics assay from SomaLogic. We used multivariable linear regression models to examine the association between proteins and each dietary pattern. Results: In the multivariable adjusted model, 276 out of 4,877 proteins (5.7%) were associated with at least one dietary pattern (AHEI: 74; aMED: 37; DASH: 250; HEI: 135; p-value &lt; 0.05/4,877=1.0х10 -5 ) ( Figure ). There were 140 proteins that were associated with only one dietary pattern (AHEI: 6; aMED: 0; DASH: 116; HEI: 18). Conclusion: Large-scale proteomic analysis identified proteins that are representative of a range of healthy dietary patterns and proteins that are specific to single healthy dietary pattern. Future studies are warranted to link diet-related proteins with clinical outcomes.
Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity
Authors: Chunhui Jiang, Mario Alberto Cano-Vega, Feng Yue, Liangju Kuang, Naagarajan Narayanan, Gozde Uzunalli, Madeline P. Merkel, Shihuan Kuang, Meng Deng
Journal: Molecular Therapy (2021)

(Molecular Therapy 25, 1718–1729; July 2017) In the originally published version of this article, the unit of serum glucose was mislabeled in Figure 6G. The correct unit should be “mM” instead of “mg/dL.” The authors regret this error. Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract ObesityJiang et al.Molecular TherapyJune 5, 2017In BriefIntegrating advances in adipocyte biology and nanotechnology, Deng, Kuang, and colleagues present a simple polymeric nanoparticle-based local delivery approach to induce browning of specific white adipose tissue depots via controlled release of a Notch inhibitor (dibenzazepine), which consequently improves the glucose homeostasis and exerts antiobesity effects in diet-induced obese mice. Full-Text PDF Open Archive