tbuckley/cabot-search huggingface dataset:
A qualitative study of the subjective experience of chemotherapy-induced nausea in cancer patients and survivors.
Authors: Ian N. Olver, Jaklin A. Eliott, Bogda Koczwara
Journal: Journal of Clinical Oncology (2012)

e19553 Background: Despite improvements in anti-emetics and reduction of chemotherapy-induced vomiting, nausea remains problematic. We hypothesize that a set of symptoms is identified by patients as nausea and these vary. Methods: Two groups of cancer patients (N = 42) with current or past experience of chemotherapy-induced nausea consented to semi-structured interviews about nausea, which were transcribed and analyzed. At interview, survivors were a median of 3.5 years (range 4 weeks – 15 y) post-treatment, median age 50 (range 25 – 80); current patients were being treated in an out-patient clinic, median age 54 (range 39 – 72). Both groups comprised 12 females and 9 males. Results: Across both groups, the nature, number, location, duration and intensity of experiences described as nausea varied; no single symptom was common to all descriptions. Physical and psychological symptoms sometimes but not always included dry-retching, vomiting, loss of appetite, indigestion, change of taste, dizziness, bloating, reflux, inability to concentrate, fatigue and physical restlessness. Location of nausea varied from head/neck, sternum, mid and lower abdomen and the whole body. Onset ranged from immediate to day 5 post-chemotherapy. Duration was from 1.5 hours to 6 months with conditioned stimuli continuing to trigger nausea 11 years post-treatment in one case. Intensity varied between and within, patients and successive treatments. For most, distinguishing features of chemotherapy-induced (as opposed to other) nausea were a constant presence over time, fatigue and emotional associations with the cancer diagnosis; for many, nausea negatively impacted on social and work interactions. Triggers also varied, and included food (smells), negative emotions including anxiety, movement, smells (e.g. hand-cream, cleaning products), treatment related events, tooth-brushing and mentioning nausea. Prescribed anti-emetics were consistently noted as reducing the intensity of, but for many, not completely alleviating, nausea; distraction and relaxation were preferred management techniques. Conclusions: Control of nausea will require personalized management of a range of physical and psychological symptoms.
Complex Polyclonal Resistance Mechanisms to Ivosidenib Monotherapy in IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia Revealed By Single Cell Sequencing Analyses
Authors: Hongfang Wang, Sung Choe, Courtney D. DiNardo, Eytan M. Stein, Stéphane de Botton, Amir T. Fathi, Martin S. Tallman, Hagop M. Kantarjian, Richard M. Stone, Lynn Quek, Vickie Zhang, Hua Liu, Eyal C. Attar, Bin Wu
Journal: Blood (2019)
Pooled safety analysis of tepotinib in Asian patients with advanced solid tumours
Authors: K. Yamazaki, B.-Y. Ryoo, T. Doi, P.K. Paik, R. Veillon, T. Decaens, S. Faivre, G.S. Falchook, D.S. Hong, J. Scheele, R. Bruns, K. Berghoff, S. Qin
Journal: Annals of Oncology (2019)
Mechanisms of orthopnoea in patients with advanced COPD
Authors: Amany F. Elbehairy, Azmy Faisal, Hannah McIsaac, Nicolle J. Domnik, Kathryn M. Milne, Matthew D. James, J. Alberto Neder, Denis E. O'Donnell
Journal: European Respiratory Journal (2020)

Many patients with severe chronic obstructive pulmonary disease (COPD) report an unpleasant respiratory sensation at rest, which is further amplified by adoption of a supine position (orthopnoea). The mechanisms of this acute symptomatic deterioration are poorly understood. Sixteen patients with advanced COPD and a history of orthopnoea and 16 age- and sex-matched healthy controls underwent pulmonary function tests (PFTs) and detailed sensory–mechanical measurements including inspiratory neural drive (IND) assessed by diaphragm electromyography (EMG di ), oesophageal pressure ( P es ) and gastric pressure ( P ga ), in both sitting and supine positions. Patients had severe airflow obstruction (forced expiratory volume in 1 s (FEV 1 ): 40±18% pred) and lung hyperinflation. Regardless of the position, patients had lower inspiratory capacity (IC) and higher IND for a given tidal volume ( V T ) ( i.e. greater neuromechanical dissociation (NMD)), higher intensity of breathing discomfort, higher minute ventilation ( V ′ E ) and higher breathing frequency ( f B ) compared with controls (all p&lt;0.05). For controls in a supine position, IC increased by 0.48 L versus sitting erect, with a small drop in V ′ E , mainly due to reduced f B (all p&lt;0.05). By contrast, IC remained unaltered in patients with COPD, but dynamic lung compliance ( C Ldyn ) decreased (p&lt;0.05) in the supine position. Breathing discomfort, inspiratory work of breathing (WOB), inspiratory effort, IND, NMD and neuroventilatory uncoupling all increased in COPD patients in the supine position (p&lt;0.05), but not in the healthy controls. Orthopnoea was associated with acute changes in IND (r=0.65, p=0.01), neuroventilatory uncoupling (r=0.76, p=0.001) and NMD (r=0.73, p=0.002). In COPD, onset of orthopnoea coincided with an abrupt increase in elastic loading of the inspiratory muscles in recumbency, in association with increased IND and greater NMD of the respiratory system.
The establishment of patient-derived organoid models and drug response of resectable non-small cell lung cancer
Authors: J.-H. Chen, X.-P. Chu, J.-T. Zhang, Q. Nie, J. Su, H.-H. Yan, H.-P. Zheng, X. Chen, M.-M. Song, L.-P. Chang, P.-S. Li, Y.-F. Guan, Y.-L. Wu, W.-Z. Zhong
Journal: Annals of Oncology (2019)
Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with advanced breast cancer (ABC): Final results from EVEREXES
Authors: Y.-H. Im, B. Karabulut, K.S. Lee, A. Adhav, B.-W. Park, H. Yesil Cinkir, J. Bowles, T Delgar Alfaro, H.L. Xue, S.-B. Kim
Journal: Annals of Oncology (2019)
Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine
Authors: Richard B. Lipton, David W. Dodick, Jessica Ailani, Kaifeng Lu, Michelle Finnegan, Armin Szegedi, Joel M. Trugman
Journal: JAMA (2019)

Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack.Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month.Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity.Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication.Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]).Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.ClinicalTrials.gov Identifier: NCT02867709.
Letter to the Editor: Does the HSD17B13 rs72613567 Splice Variant Actually Yield a New Type of Alternative Splicing?
Authors: Enrico Galmozzi
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: I read with great interest the article by Ma et al.1 evaluating which of the 38 single‐nucleotide polymorphisms (SNPs) associated with liver enzymes in the general population correlated with histological features in a cohort of 768 whites with nonalcoholic fatty liver disease (NAFLD). They concluded that rs6834314, rs72613567, and rs62305723 variants in the 17‐beta hydroxysteroid dehydrogenase 13 (HSD17B13) gene were associated with specific features of NAFLD histology. In particular, the investigators show that the rs72613567 SNP, located in the 5′ splice site (5′ss) consensus sequence of intron 6, generates two simultaneously expressed splice isoforms that are also devoid of enzymatic function. One of the isoforms contains exon 6 skipping (delta‐6) and the other a single G‐nucleotide insertion (G insertion) between exons 6 and 7, producing a frameshift and premature stop codon (PTC). I believe this point requires clarification. First, whereas mutations in the 5′ss consensus sequence mainly cause skipping of the exon that precedes it as well as cryptic splice‐site activation and intron retention, which is rarer, no insertion of a single nucleotide has yet been reported.2 Second, recent mutational analyses demonstrated that certain presumptively weak 5′ss consensus, such as that obtained in the presence of the rs72613567 splice variant (i.e., GUUAAGU), can be used by alternative base pairing, collectively termed "bulge registers."3 Third, the presence of PTC in the transcript, also in the 3′ untranslated region (UTR), usually leads to faster mRNA degradation during a protective process called "nonsense‐mediated decay."4 Therefore, the presence of the HSD17B13 delta‐6 isoform agrees with the literature data, unlike the G insertion, which should also be questioned because of the specificity of primers described by the investigators. Indeed, the direction of the HSD17B13‐G insertion primers pair designated for the first amplification step was wrong, and the reverse primer of the second step did not map on HSD17B13 mRNA (Fig. 1). Accordingly, no correct amplification of the G‐insertion isoform was possible. Finally, because the presence of the HSD17B13 G‐insertion transcript has been described only in one other article to date,5 this new mechanism of alternative splicing needs further validations.Figure 1: Schematic alignment of the HSD17B13‐G insertion primers reported by Ma et al.1 in Supporting Table S12.
Lipotoxic Hepatocyte‐Derived Exosomal MicroRNA 192‐5p Activates Macrophages Through Rictor/Akt/Forkhead Box Transcription Factor O1 Signaling in Nonalcoholic Fatty Liver Disease
Authors: Xiao‐Lin Liu, Qin Pan, Hai‐Xia Cao, Feng‐Zhi Xin, Ze‐Hua Zhao, Rui‐Xu Yang, Jing Zeng, Huiping Zhou, Jian‐Gao Fan
Journal: Hepatology (2019)

Hepatic macrophages can be activated by many factors such as gut-derived bacterial components and factors released from damaged hepatocytes. Macrophage polarization toward a proinflammatory phenotype (M1) represents an important event in the disease progression of nonalcoholic fatty liver disease (NAFLD). However, the underlying molecular mechanisms remain incompletely understood. Exosomes have been identified as important mediators for cell-cell communication by transferring various biological components such as microRNAs (miRs), proteins, and lipids. The role of exosomes in crosstalk between hepatocytes and macrophages in disease progression of NAFLD is yet to be explored.In the present study, we reported that lipotoxic injury-induced release of hepatocyte exosomes enriched with miR-192-5p played a critical role in the activation of M1 macrophages and hepatic inflammation. Serum miR-192-5p levels in patients with NAFLD positively correlated with hepatic inflammatory activity score and disease progression. Similarly, the serum miR-192-5p level and the number of M1 macrophages, as well as the expression levels of the hepatic proinflammatory mediators, were correlated with disease progression in high-fat high-cholesterol diet-fed rat models. Lipotoxic hepatocytes released more miR-192-5p-enriched exosomes than controls, which induced M1 macrophage (cluster of differentiation 11b-positive [CD11b+ ]/CD86+ ) activation and increase of inducible nitric oxide synthase, interleukin 6, and tumor necrosis factor alpha expression. Furthermore, hepatocyte-derived exosomal miR-192-5p inhibited the protein expression of the rapamycin-insensitive companion of mammalian target of rapamycin (Rictor), which further inhibited the phosphorylation levels of Akt and forkhead box transcription factor O1 (FoxO1) and resulted in activation of FoxO1 and subsequent induction of the inflammatory response.Hepatocyte-derived exosomal miR-192-5p plays a critical role in the activation of proinflammatory macrophages and disease progression of NAFLD through modulating Rictor/Akt/FoxO1 signaling. Serum exosomal miR-192-5p represents a potential noninvasive biomarker and therapeutic target for nonalcoholic steatohepatitis.
Overall Survival with Osimertinib in Untreated, <i>EGFR</i>-Mutated Advanced NSCLC
Authors: Suresh S. Ramalingam, Johan Vansteenkiste, David Planchard, Byoung Chul Cho, Jhanelle E. Gray, Yuichiro Ohe, Caicun Zhou, Thanyanan Reungwetwattana, Ying Cheng, Busyamas Chewaskulyong, Riyaz Shah, Manuel Cobo, Ki Hyeong Lee, Parneet Cheema, Marcello Tiseo, Thomas John, Meng-Chih Lin, Fumio Imamura, Takayasu Kurata, Alexander Todd, Rachel Hodge, Matilde Saggese, Yuri Rukazenkov, Jean-Charles Soria
Journal: New England Journal of Medicine (2019)

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported.
SPOTLIGHT: Comparison of zolbetuximab or placebo + mFOLFOX6 as first-line treatment in patients with claudin18.2+/HER2– locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ): A randomized phase III study
Authors: K. Yamaguchi, K. Shitara, S.-E. Al-Batran, Y.-J. Bang, D. Catenacci, P. Enzinger, D. Ilson, S. Kim, F. Lordick, M. Shah, E. Van Cutsem, R.-H. Xu, A. Arozullah, J. Wook Park, J. Ajani
Journal: Annals of Oncology (2019)
Paclitaxel-resistant MCF-7 cells show a caspase-less phenotype but retain sensitivity to many anticancer agents
Authors: Ghada Ajabnoor, Patricia Macanas-Pirard, Christine Shotton, Helen Coley
Journal: Cancer Research (2008)

2657  Anticancer drug resistance occurs as a result of altered response to cytotoxic insult, particularly via inhibition or inactivation of apoptosis (programmed cell death type I, PCDI), and plays a major role in tumour development and progression. An alternative form of cell death - non-apoptotic or autophagic cell death (PCDII) has recently emerged as a factor contributing to the cytotoxic response of cancer cells. We have studied cell death in a drug resistant model MCF-7 human breast cancer cells with acquired resistance (c. 20-fold) to paclitaxel termed MCF-7TaxR. This novel cell line was generated by us in-house. It has been reported that the absence of caspase-3 in parent MCF-7 cells (due to chromosome deletion) may explain why this cell line recruits both apoptotic and autophagic cell death mechanisms following cytotoxic insult. Considering the mitochondrial pathway of apoptosis we detected caspase-9 protein in MCF-7 cells but a total absence in MCF-7TaxR (western blotting), confirmed by PCR analysis for mRNA levels. Interestingly, MCF-7TaxR was shown to over-express the MDR transporter P-glycoprotein (western blot). However, MTT cell viability assay indicated that MCF-7TaxR cells showed a marked lack of cross-resistance to a range of agents such as VP-16, doxorubicin and vinblastine, contrary to the MDR phenotype. In addition, MCF-7TaxR displayed collateral sensitivity to carboplatin and cisplatin relative to the parental MCF-7 cells i.e. IC50values for carboplatin: MCF-7TaxR 26.0 µM; MCF-7 84.0 µM; for cisplatin: MCF-7TaxR 7.5 µM; MCF-7 17.0 µM. Apoptotic response was examined by flow cytometry (Annexin-V with propidium iodide) by treating MCF-7, MCF-7TaxR and MB-231 (caspase-proficient control) breast cancer cells with 0.5 µM staurosporine together with the pan-caspase inhibitor Z-VAD (100 µM ). Results showed the ability of staurosporine to induce caspase-mediated apoptosis in breast cancer cells was of the order: MB-231>>MCF-7>> MCF-7TaxR. Further western blot analysis revealed an absence of caspase-7 in MCF-7TaxR, with DNA microarray analysis and q-PCR confirming the absence of caspase mRNA. Given the constitutive absence of caspase-3 in MCF-7 and the variant MCF-7TaxR cells, we would describe the MCF-7TaxR cells as “caspase-less”. Hence, we have tried to look for the presence of autophagic cell death in our MCF-7TaxR line. Flow cytometry with acridine orange to detect the presence of autophagic cell death (preincubation with 0.5µM staurosporine and 200-500nM bafilomycin as autophagy inhibitor) showed evidence of autophagy in MCF-7 cells, with a greater response in MCF-7TaxR cells. Collectively, these finding indicate for the first time the lack of involvement of caspase-mediated cell death in a taxane-resistant cancer cell line, with otherwise retained drug sensitivity, due to alternative cell death mechanisms.
Treatment of Primary Plasma Cell Leukemia with Carfilzomib and Lenalidomide-Based Therapy: Results of the First Interim Analysis of the Phase 2 EMN12/HOVON129 Study
Authors: Niels W. C. J. Van De Donk, Bronno van der Holt, Fredrik H. Schjesvold, Ka Lung Wu, Stefano Spada, Annemiek Broyl, Wilfried Roeloffzen, Alain Gaddiseur, Thomas Lund, Monique C. Minnema, Massimo Offidani, Mariella Grasso, Niels Frost Andersen, Jo Caers, Benedetto Bruno, Sonja Zweegman, Pieter Sonneveld, Roman Hajek, Reuben Benjamin, Francesca Gay, Annette Juul Vangsted, Pellegrino Musto
Journal: Blood (2019)
Fedratinib Induces Spleen Responses and Reduces Symptom Burden in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Low Platelet Counts, who were Either Ruxolitinib-Naïve or were Previously Treated with Ruxolitinib
Authors: Claire N Harrison, Nicolaas Schaap, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Francesco Passamonti, Sonja Zweegman, Moshe Talpaz, Srdan Verstovsek, Shelonitda Rose, Jun Zhang, Tymara Berry, Carrie Brownstein, Ruben A Mesa
Journal: Blood (2019)
Oral adherence in adults with acute myeloid leukemia (AML): Results of a mixed methods study.
Authors: Ashley Leak Bryant, Thomas William LeBlanc, Tara A. Albrecht, Ya-Ning Chan, Jaime Richardson, Matthew C. Foster, Malisa Dang, Susie Owenby, Debra Wujcik
Journal: Journal of Clinical Oncology (2019)

105 Background: The incidence of AML is increasing, in part due to an aging population. Amid established intravenous (IV) or subcutaneous chemotherapies , recent drug approvals have ushered in an era of oral medication (OM) approaches to treating AML, shifting the burden of daily adherence from clinicians to patients. We aimed to identify and summarize adherence to oral therapy in this population. Methods: Our mixed methods study design used focus groups (FG) and patient surveys. After IRB approval, 11 patients and 4 caregivers participated in 4 focus groups. Results were used to develop a 37-item OM adherence needs assessment. Subsequently, AML patients were recruited and consented at three cancer centers to complete surveys (online, at the clinic, hospital, or from home). Results: 100 patients completed the OM survey. Most were male (62%), racial/ethnic diversity (33%), &lt; 65 years (59%), and college-educated (52%). The to be taken was the most frequent and troublesome challenge. Loss of appetite was the most commonly reported and problematic side effect. Although half of the patients stated, “no side effect would cause them to stop taking OM”, another 25% indicated nausea would cause non-adherence. The best strategy to support taking OM was to make it part of the daily routine. Directions for taking OM were most commonly found on medication bottles or received from the health care team (HCT); patients felt HCTs were the best source of directions. Nearly 1/3 of patients indicated they skip the OM dose altogether when they forget to take it. When asked what would help improve adherence: smaller pills, easier packaging, and scheduling assistance were most frequently reported. Older individuals (&gt;65 years) had a slightly more positive attitude towards oral medication (p =.51). Younger patients (&lt;65 years) were more accepting of taking oral vs IV meds, (p = .03). Conclusions: This study represents the first assessment of OM adherence in patients with AML. Three themes emerged in FG transcript analysis that informed the development of a 37-item survey that was subsequently completed by 100 patients. Findings provide the basis for further exploration of interventions to enhance and increase adherence to OM regimens.
Addressing the context and consequences of substance use, misuse, and dependence: A global imperative
Authors: Alexander C. Tsai, Margarita Alegría, Steffanie A. Strathdee
Journal: PLoS Medicine (2019)

Substance use, misuse, and dependence contribute immensely to the global burden of disease [1].Their harms extend far beyond their corrosive effects on health, safety, and wellbeing and additionally include those associated with healthcare expenditures, productivity losses, criminal justice involvement, and other negative effects on social welfare [2].The incidence and harms of substance use, misuse, and dependence involve multilevel explanatory factors [3,4].Interventions to reduce their individual-and population-level harms can often be hampered by biological, psychological, and social complexity, especially because substance use is often syndemic with other health and social problems such as HIV infection, hepatitis B and C, mental health disorders, and violence [5,6].It is in this context that PLOS Medicine devotes its November 2019 Special Issue to research on substance use, misuse, and dependence.The contributions to the issue cover a wide range of topics, including social determinants of substance use, health harms resulting from substance use, and interventions to prevent or reduce the harms associated with substance use.There are also a number of gaps in terms of the topics covered, the robustness of the evidence, and its global scope.