bluuebunny/crossref_metadata_2025_split huggingface dataset:
A First-in-Human, Phase I, Multicenter, Open-Label, Dose-Escalation Study of PCA062: An Antibody–Drug Conjugate Targeting P-Cadherin, in Patients With Solid Tumors
Authors: Duca Matteo , Lim Darren Wan-Teck , Subbiah Vivek , Takahashi Shunji , Sarantopoulos John , Varga Andrea , D'Alessio Joseph A. , Abrams Tinya , Sheng Qing , Tan Eugene Youchin , Rosa Maria Santos , Gonzalez-Maffe Juan , Sand-Dejmek Janna , Fabre Claire , Martin Miguel 
Published: February 2022

Abstract
This first-in-human (FIH), phase I, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the MTD/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors. Adult patients with any solid tumor type and having a documented P-cadherin–positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE.
Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg every 2 weeks administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg every 2 weeks and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P-cadherin–related toxicities. Pharmacokinetics was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy. Because of limited antitumor activity at the MTD level, Novartis has terminated clinical development of PCA062 (NCT02375958).
Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements
Authors: Schram Alison M. , Odintsov Igor , Espinosa-Cotton Madelyn , Khodos Inna , Sisso Whitney J. , Mattar Marissa S. , Lui Allan J.W. , Vojnic Morana , Shameem Sara H. , Chauhan Thrusha , Torrisi Jean , Ford Jim , O'Connor Marie N. , Geuijen Cecile A.W. , Schackmann Ron C.J. , Lammerts van Bueren Jeroen J. , Wasserman Ernesto , de Stanchina Elisa , O'Reilly Eileen M. , Ladanyi Marc , Drilon Alexander , Somwar Romel 
Published: February 2022

Abstract

NRG1 rearrangements are recurrent oncogenic drivers in solid tumors. NRG1 binds to HER3, leading to heterodimerization with other HER/ERBB kinases, increased downstream signaling, and tumorigenesis. Targeting ERBBs, therefore, represents a therapeutic strategy for these cancers. We investigated zenocutuzumab (Zeno; MCLA-128), an antibody-dependent cellular cytotoxicity–enhanced anti-HER2xHER3 bispecific antibody, in NRG1 fusion–positive isogenic and patient-derived cell lines and xenograft models. Zeno inhibited HER3 and AKT phosphorylation, induced expression of apoptosis markers, and inhibited growth. Three patients with chemotherapy-resistant NRG1 fusion–positive metastatic cancer were treated with Zeno. Two patients with ATP1B1–NRG1–positive pancreatic cancer achieved rapid symptomatic, biomarker, and radiographic responses and remained on treatment for over 12 months. A patient with CD74–NRG1-positive non–small cell lung cancer who had progressed on six prior lines of systemic therapy, including afatinib, responded rapidly to treatment with a partial response. Targeting HER2 and HER3 simultaneously with Zeno is a novel therapeutic paradigm for patients with NRG1 fusion–positive cancers.

Significance:
NRG1 rearrangements encode chimeric ligands that activate the ERBB receptor tyrosine kinase family. Here we show that targeting HER2 and HER3 simultaneously with the bispecific antibody Zeno leads to durable clinical responses in patients with NRG1 fusion–positive cancers and is thus an effective therapeutic strategy.
This article is highlighted in the In This Issue feature, p. 1171
Longe da mera ficção
Authors: Menger Jonathan Bernardo 
Published: February 2022

O texto objetiva fazer uma análise crítico-comparativa entre duas obras estrangeiras que discorrem sobre os terrores do nazismo na 2ª Guerra, trazendo possíveis reflexões para os dias atuais.

BOYNE, John. O menino do pijama listrado. São Paulo: Seguinte, 2016.
DOWSWELL, Paul. O órfão de Hitler. São Paulo: Planeta, 2016.
Prevalence of idiopathic osteosclerosis in the mandible: a cone beam computed tomography study
Authors: Mehdizadeh Mojdeh , Firoozi Farnoush , Soltani Parisa 
Published: February 2022

Objective: The aim of this study is to determine the prevalence of idiopathic osteosclerosis (IO) in the mandible in an Iranian subpopulation using cone beam computed tomography (CBCT). Methods: This cross-sectional study was performed on all CBCT images obtained in 2010-2014 from the archive of Oral and Maxillofacial Radiology Department at Isfahan Dental School. Images were evaluated by two observers in identical room and monitoring conditions. IO was defined as homogenous radiopacities with no particular etiology, ranging from 2 mm to 2 cm in size. Demographic information of all patients, as well as the lesion’s number, location, border, shape, and association with adjacent teeth were recorded. Results: From 377 CBCT images, 43 images (11.4%) had at least one IO lesion. Two separate IO lesions were detected in six patients; therefore, 49 IO lesions were found in total. No gender differences were observed in IO prevalence (P = 0.806). Although most common in patients who were in their 30s, IO prevalence was not statistically different among age groups (P = 0.369). IO was most frequent in the molar region, with 63.2% of lesions. Conclusion: IO prevalence was 11.4% in the studied population and was not statistically different between age groups or sexes. Most lesions were found in the mandibular molar region.
Bandersnatch: uma crítica de processo
Authors: Estorillio Rodrigo dos Santos 
Published: February 2022

A complexa sistematização das narrativas interativas se processa nas inovações homem-máquina, potencializadas pelo uso de ferramentas tecnológicas que manipulam interfaces de aplicativos hipermidiáticos, modelando scripts em linguagem HTML que se traduzem em conceitos narratológicos e conteúdo multitrama aos usuários em plataformas e redes de comunicação. O recorte desta pesquisa parte do processo de criação hipertextual em multitrama, Bandersnatch, e seu tratamento em roteiro de longa-metragem de ficção interativa. A sistematização narratológica gravita um processo de readequação estrutural por conta das potencialidades interativas que o meio digital on-line propicia ao interator na fruição do filme-jogo. O fenômeno ocorre conforme um menor ou maior grau de abertura da obra ou compartilhamento indicial de autoria, em que a dimensão multilinear da história provoca cognitivamente o sistema nervoso por meio do “envolvimento extensivo do corpo na sua globalidade psicossensorial, sinestésica”[1] (SANTAELLA, 2010). Objetivo demonstrar como a manipulação dos elementos estruturais dos mundos ficcionais da narrativa interativa revela a multidimensionalidade do real frente às relações entre o virtual e o atual, operando complexidades intersemióticas por meio dos fenômenos de linguagem e signagens.
[1] SANTAELLA, L. Culturas e artes do pós-humano: da cultura das mídias à cibercultura. 4ª ed.. São Paulo: Editora Paulus, 2010, p. 227.

[1] SANTAELLA, Lúcia. Culturas e artes do pós-humano: da cultura das mídias à cibercultura. 4ª ed.. São Paulo: Editora Paulus, 2010, p. 227.
Genome-Wide Characterization of a Highly Penetrant Form of Hyperlipoprotein(a)emia Associated With Genetically Elevated Cardiovascular Risk
Authors: Coassin Stefan , Chemello Kevin , Khantalin Ilya , Forer Lukas , Döttelmayer Patricia , Schönherr Sebastian , Grüneis Rebecca , Chong-Hong-Fong Clément , Nativel Brice , Ramin-Mangata Stéphane , Gallo Antonio , Roche Mathias , Mühlegger Beatrix , Gieger Christian , Peters Annette , Zschocke Johannes , Marimoutou Catherine , Meilhac Olivier , Lamina Claudia , Kronenberg Florian , Blanchard Valentin , Lambert Gilles 
Published: February 2022

Background:
Lp(a) (lipoprotein [a]) is a highly atherogenic lipoprotein strongly associated with coronary artery disease (CAD). Lp(a) concentrations are chiefly determined genetically. Investigation of large pedigrees with extreme Lp(a) using modern whole-genome approaches may unravel the genetic determinants underpinning this pathological phenotype.

Methods:
A large family characterized by high Lp(a) and increased CAD incidence was recruited by cascade screening. Plasma lipids, lipoproteins, and apolipoproteins concentrations, as well as the size of apo(a) isoforms, were determined enzymatically by high-resolution mass spectrometry and Western blot, respectively. Whole-exome sequencing was performed to search for rare defects in modifier genes. Genetic risk scores (GRS) for Lp(a) and CAD were calculated and their discriminative power was assessed.

Results:

Seventeen individuals displayed extreme Lp(a) levels including 6 with CAD. Whole-exome sequencing showed no hint for genetic defects outside the
LPA
locus. The extreme Lp(a) phenotype segregated with the presence of a short apo(a) isoform containing 21 Kringle IV domains. This allele was characterized by the presence of three rare strongly Lp(a) increasing single nucleotide polymorphisms and a significantly increased load of oxidized phospholipids per Lp(a) particle. An Lp(a) GRS consisting of 48 single nucleotide polymorphisms that represent 2001 genome-wide significant
LPA
single nucleotide polymorphisms, efficiently captured the hyper-Lp(a) phenotype and discriminated affected and nonaffected individuals with great accuracy. The genome-wide GRS for CAD, encompassing 6.6 million single nucleotide polymorphisms, was very high for most family members (>97.5 percentile of the reference population), but this observation was no longer valid when the contribution of the
LPA
locus was omitted.

Conclusions:

High-Lp(a) phenotypes can be successfully captured using the Lp(a) GRS even among closely related family members. In hyper-Lp(a) individuals,
LPA
can be a major locus driving a very high CAD GRS. This underpins the large contribution of the
LPA
locus to the cardiovascular genetic risk in families.
Five-Year Outcomes After Fractional Flow Reserve–Based Deferral of Revascularization in Chronic Coronary Syndrome: Final Results From the J-CONFIRM Registry
Authors: Kuramitsu Shoichi , Matsuo Hitoshi , Shinozaki Tomohiro , Horie Kazunori , Takashima Hiroaki , Terai Hidenobu , Kikuta Yuetsu , Ishihara Takayuki , Saigusa Tatsuya , Sakamoto Tomohiro , Suematsu Nobuhiro , Shiono Yasutsugu , Asano Taku , Tsujita Kenichi , Masamura Katsuhiko , Doijiri Tatsuki , Toyota Fumitoshi , Ogita Manabu , Kurita Tairo , Matsuo Akiko , Harada Ken , Yaginuma Kenji , Sonoda Shinjo , Yokoi Hiroyoshi , Tanaka Nobuhiro ,   on behalf of the J-CONFIRM Investigators
Published: February 2022

Background:
Little large-scale data is available about the long-term (beyond 3 years) clinical outcomes after fractional flow reserve (FFR)–based deferral of revascularization in clinical practice. We sought to assess the 5-year outcomes after deferral of revascularization based on FFR.

Methods:
The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR from 28 Japanese centers. The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), including cardiac death, target vessel–related myocardial infarction, and clinically driven target vessel revascularization.

Results:

Five-year follow-up was completed in 92.2% of patients. The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization (9.8%). Cardiac death and target vessel–related myocardial infarction were 1.9% and 0.95%, respectively. Cumulative 5-year incidence of TVF was similar between the FFR 0.75 to 0.80 and 0.81 to 0.85 groups even after adjustment for baseline characteristics (12.2% versus 13.0%, inverse probability–weighted hazard ratio, 0.86 [95% CI, 0.46–1.60];
P
=0.63). Compared with the almost normal FFR (0.86–1.00) group, the significant (<0.75) and borderline (0.75–0.85) FFR groups showed a higher incidence of TVF at 5 years (29.9% versus 12.8% versus 8.6%,
P
<0.001). Independent predictors of the 5-year TVF were hemodialysis, FFR value, left main coronary artery lesion, prior percutaneous coronary intervention, and male sex.

Conclusions:
The 5-year TVF rate was 11.6% in deferred lesions, mainly driven by clinically driven target vessel revascularization. Notably, cardiac death and target vessel–related myocardial infarction rarely occurred during the follow-up. Our findings highlight the long-term safety of FFR-based deferral of revascularization in patients with chronic coronary syndrome.

Registration:

URL:
https://www.umin.ac.jp/ctr
; Unique identifier: UMIN000014473.
Coronary Revascularization Versus Optimal Medical Therapy in Renal Transplant Candidates With Coronary Artery Disease: A Systematic Review and Meta‐Analysis
Authors: Siddiqui Muhammad U. , Junarta Joey , Marhefka Gregary D. 
Published: February 2022

Background
Coronary artery disease (CAD) is highly prevalent in patients with chronic kidney disease and is a common cause of mortality in end‐stage renal disease. Thus, patients with end‐stage renal disease are routinely screened for CAD before renal transplantation. The usefulness of revascularization before transplantation remains unclear. We hypothesize that there is no difference in all‐cause and cardiovascular mortality in waitlisted renal transplant candidates with CAD who underwent revascularization versus those treated with optimal medical therapy before transplantation.

Methods and Results

This meta‐analysis was reported according to the
Preferred Reporting Items for Systematic Review and Meta‐Analyses
guidelines. MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. Risk of bias was assessed using the modified Newcastle‐Ottawa Scale and Cochrane risk of bias tool. The primary outcome of interest was all‐cause mortality. Eight studies comprising 945 patients were included (36% women, mean age 56 years). There was no difference in all‐cause mortality (risk ratio [RR], 1.16 [95% CI, 0.63–2.12), cardiovascular mortality (RR, 0.75 [95% CI, 0.29–1.89]), or major adverse cardiovascular events (RR, 0.78 [95% CI, 0.30–2.07]) when comparing renal transplant candidates with CAD who underwent revascularization versus those who were on optimal medical therapy before renal transplant.

Conclusions
This meta‐analysis demonstrates that revascularization is not superior to optimal medical therapy in reducing all‐cause mortality, cardiovascular mortality, or major adverse cardiovascular events in waitlisted kidney transplant candidates with CAD who eventually underwent kidney transplantation.
ABCD‐GENE Score and Clinical Outcomes Following Percutaneous Coronary Intervention: Insights from the TAILOR‐PCI Trial
Authors: Capodanno Davide , Angiolillo Dominick J. , Lennon Ryan J. , Goodman Shaun G. , Kim Sang‐Wook , O'Cochlain Fearghas , So Derek Y. , Sweeney John , Rihal Charanjit S. , Farkouh Michael , Pereira Naveen L. 
Published: February 2022

Background

In TAILOR‐PCI, genotype‐guided selection of P2Y
12
inhibitors after percutaneous coronary intervention did not significantly reduce the risk of ischemic events at 12 months. The Age, Body Mass Index, Chronic Kidney Disease, Diabetes, and Genotyping (ABCD‐GENE) score identifies patients with high platelet reactivity on clopidogrel at increased risk of ischemic events. The aim of this study was to investigate the value of the ABCD‐GENE score for tailoring P2Y
12
inhibitor selection after percutaneous coronary intervention.

Methods and Results

In a post hoc analysis of the TAILOR‐PCI, outcomes were analyzed by ABCD‐GENE score and allocation to genotype‐guided or conventional P2Y
12
inhibitor selection. Primary (death, myocardial infarction, or stroke) and secondary (cardiovascular death, myocardial infarction, stroke, stent thrombosis, or severe recurrent ischemia) outcomes were assessed. Among 3883 patients discharged on clopidogrel in the genotype‐guided and conventional therapy groups, 15.8% and 84.2% had high (≥10 points) or low (<10) ABCD‐GENE scores, respectively. At 12 months, both the primary (5.2% versus 2.6%,
P
<0.001) and secondary outcomes (7.7% versus 4.6%,
P
=0.001) were significantly increased in patients with high ABCD‐GENE score. Among 4714 patients allocated to genotype‐guided or conventional therapy, the former did not significantly reduce the 12‐month risk of the primary and secondary outcomes in both the high and low ABCD‐GENE score groups (p
interaction
=0.48 and 0.27, respectively).

Conclusions

Among patients with percutaneous coronary intervention on clopidogrel, the ABCD‐GENE score was helpful in identifying those at higher risk. The ABCD‐GENE score may potentially enhance the precision of tailored selection of P2Y
12
inhibitors, which needs to be confirmed in prospective investigations.

Clinical Trial Registration

URL:
http://www.clinicaltrials.gov
. Unique Identifier: NCT01742117.
A new species of sublittoral marine copepod, Normanella parvisetosa sp. nov. (Harpacticoida, Normanellidae), from the Southern Sea of South Korea
Authors: Kim Jong Guk , Kim Sung Hoon , Yoon Seong Myeong 
Published: February 2022

Abstract
A new harpacticoid species, Normanella parvisetosa sp. nov., belonging to the family Normanellidae Lang, 1944, is described from subtidal habitats in the Southern Sea of South Korea. This new species is assigned to the minuta-lineage, based on the rostrum with a pointed apical tip, the five-segmented female antennule, the female P5 exopod without a distinct notch on the outer margin, and well-developed caudal setae IV and V each bearing an internal fracture plane. Normanella parvisetosa sp. nov. is morphologically close to N. incerta Lang, 1934, N. porosa Noodt, 1964, and N. obscura Lee & Huys, 1999, whereas the new species is distinguished from females of these species in the shape of the rostrum with a pointed tip, the relative length to width ratio of the caudal rami, the second endopodal segment of the second to fourth legs, the exopod of the fifth leg, and the relative length of setae on both rami of the fifth leg. Herein, we provide a detailed description and illustrations of Normanella parvisetosa sp. nov., which is the second Normanella species identified in Korean waters.
FDI Policy in India: With Special Reference to the Multi-Brand Retail FDI Policy
Authors: Chakraborty Paromita 
Published: February 2022

This article attempts to trace the FDI policy in India from India’s Independence till the economic liberalisation in 1991 and onwards. It highlights how different regimes approached the FDI policy in India, from ‘hostility’ to ‘accommodation’ to ‘collaboration’. The article then looks at the multi-brand retail FDI policy which was recently introduced in India. This policy was one of the hallmarks of the United Progressive Alliance (UPA II) regime and marked a significant push towards a more extensive economic reforms programme. It clearly stated that if this policy is operationalised, it will result in a big boost in investments in our country. However, most of the Indian states, the Left parties and various regional parties opposed the introduction of FDI in the multi-brand retail sector. They stated that this policy would harm the Indian economy in the long run. The article also focuses on two important stakeholders of this policy, namely the farming sector and the unorganised retailers. It looks at the advantages and the disadvantages of the multi-brand retail FDI policy on these two sectors along with their responses.
Patient‐Defined Goals for Obstructive Sleep Apnea Treatment
Authors: Cai Yi , Tripuraneni Priyanka , Gulati Arushi , Stephens Erika M. , Nguyen Dang‐Khoa , Durr Megan L. , Chang Jolie L. 
Published: February 2022

ObjectivesTo characterize the treatment goals and values of adult patients with obstructive sleep apnea (OSA).Study DesignMixed methods design based on semistructured interviews followed by cross‐sectional surveys.SettingAcademic medical center and integrated managed care consortium.MethodsPhase 1 involved qualitative analysis of focus groups and interviews to define treatment goal categories. Phase 2 included analysis of cross‐sectional surveys on most important treatment goals from patients with OSA presenting to sleep surgery clinic. Positive airway pressure (PAP) use, Epworth Sleepiness Scale score, and apnea‐hypopnea index were obtained to determine influences on goal choices.ResultsDuring focus groups and interviews, treatment goal themes identified included improving sleep quality, reducing daytime sleepiness, snoring sound reduction, and health risk reduction. In phase 2, 536 patients were surveyed, and they reported the primary treatment goals of health risk reduction (35%), sleep quality improvement (28%), daytime sleepiness improvement (21%), and snoring sound reduction (16%). The primary treatment goal was associated with age (P <. 0001), excessive daytime sleepiness (Epworth Sleepiness Scale score >10, P <. 0001), PAP use status (P <. 0001), and OSA severity (apnea‐hypopnea index, P <. 0001). Severity of OSA was associated with increasing proportion of patients choosing health risk reduction as the main treatment goal (P <. 05).ConclusionsAdult OSA treatment goal choices vary with age, symptoms, PAP history, and OSA severity. Understanding patient‐specific goals is the essential first step in the shared decision‐making process when choosing surgical or nonsurgical treatments. Ultimately, goal‐focused discussions ensure alignment of priorities and definitions of success between the patient and the provider.
Cost‐effectiveness of Canal Wall‐Up vs Canal Wall‐Down Mastoidectomy: A Modeling Study
Authors: Bu Daniel D. , Schwam Zachary G. , Kaul Vivian F. , Wong Kevin , Fan Caleb , Wanna George B. , Cosetti Maura K. , Perez Enrique 
Published: February 2022

ObjectiveTo assess the relative lifetime costs, benefits, and cost‐effectiveness between the 2 approaches, canal wall‐up (CWU) and canal wall‐down (CWD) tympanomastoidectomy, used in the treatment of cholesteatomas.Study DesignMarkov state transition model.SettingTertiary academic health system.MethodsA Markov state transition model was used to simulate outcomes across the patient lifetime. Outcome and complication probabilities were obtained from the existing literature. Costs were calculated from the payer perspective, with procedure, hospital, clinic, and physician cost derived from Medicare reimbursement. Quality‐adjusted life years (QALYs) were used to represent effectiveness and utility. One‐way and probability sensitivity analyses (PSAs) were conducted.ResultsThe base case analysis, assuming a 40‐year‐old patient, yielded a lifetime cost of $14,214 for a patient treated with the CWU approach assuming second‐look surgery and $22,290 with a CWD approach. CWU and CWD generated a benefit of 17.11 and 17.30 QALYs, respectively. The incremental cost‐effectiveness ratio for CWU was $43,237 per QALY. The Monte Carlo PSA validated the base case scenario. Using a standard $50,000 willingness‐to‐pay threshold, CWD was the more cost‐effective approach and was selected 54.8% of the time by the simulation.ConclusionBoth CWU and CWD were found to be cost‐effective, with CWD being cost‐effective 54.8% of the time at a WTP threshold of $50,000. The assumptions used in the analysis were validated by the results of 1‐way and PSA.