bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and tolerability of andecaliximab as monotherapy and in combination with an anti-PD-1 antibody in Japanese patients with gastric or gastroesophageal junction adenocarcinoma: a phase 1b study
Authors: Yoshikawa Akie Kimura , Yamaguchi Kensei , Muro Kei , Takashima Atsuo , Ichimura Takashi , Sakai Daisuke , Kadowaki Shigenori , Chin Keisho , Kudo Toshihiro , Mitani Seiichiro , Kitano Shigehisa , Thai Dung , Zavodovskaya Marianna , Liu JieJane , Boku Narikazu , Satoh Taroh 
Published: January 2022

BackgroundMatrix metalloproteinase 9 (MMP9) is implicated in protumorigenic processes. Targeting either stromal or epithelial MMP9 reduces the incidence of metastasis. Andecaliximab is a monoclonal antibody that targets MMP9 with high affinity and selectivity. However, no study has examined whether the inhibition of T-cell programmed death 1 (PD-1) in the presence of andecaliximab increases activated lymphocyte infiltration into the tumor, thereby increasing antitumor activity more than that in anti-PD-1 monotherapy. In this study, we assessed the safety, pharmacokinetics (PK), exploratory biomarkers, and preliminary efficacy of andecaliximab as monotherapy and in combination with nivolumab in Japanese patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) adenocarcinoma.MethodsThis phase 1b study comprised four cohorts enrolling Japanese patients with gastric or GEJ adenocarcinoma. This paper concerns cohorts 1 and 4; cohorts 2 and 3 will be reported subsequently. Cohort 1 enrolled patients with human epidermal growth factor receptor 2 (HER2)-negative tumors (n=8) who received andecaliximab monotherapy (800 mg by intravenous infusion every 2 weeks (Q2W)), and cohort 4 enrolled patients irrespective of their HER2 status (n=10) who received 800 mg of andecaliximab in combination with nivolumab Q2W. Safety, dose-limiting toxicities (DLTs), PK, pharmacodynamics, and biomarkers were assessed in both cohorts.ResultsPK of andecaliximab in Japanese patients with gastric or GEJ adenocarcinoma was similar to that reported in non-Japanese patients with advanced solid tumors. Andecaliximab monotherapy and in combination with nivolumab demonstrated no DLTs in cohort 1 and 4, respectively. Toxicities were manageable and well tolerated in both cohorts. The median progression-free survival was 1.4 months (90% CI, 0.5 to 5.4) and 4.6 months (90% CI, 0.9 to not reached) in cohorts 1 and 4, respectively. The objective response rate was 50% (90% CI, 22% to 78%) in cohort 4, and in some patients, the combination therapy was effective regardless of the biomarker status.ConclusionsThe andecaliximab–nivolumab combination demonstrated a manageable safety profile and promising clinical activity in patients with advanced gastric adenocarcinoma.NCT02862535.
Differences between sperm sharing and egg sharing are morally relevant
Authors: Hodson Nathan 
Published: January 2022

Sperm sharing arrangements involve a man (‘the sharer’) allowing his sperm to be used by people seeking donor sperm (‘the recipients’) in exchange for reduced price in vitro fertilisation. Clinics in the UK have offered egg sharing since the 1990s and the arrangement has been subjected to regulatory oversight and significant ethical analysis. By contrast, until now no published ethical or empirical research has analysed sperm sharing. Moreover the Human Fertilisation and Embryology Authority (HFEA) does not record the number of sperm sharing arrangements taking place.This paper describes the sperm sharing process providing an analysis of all the UK clinics advertising sperm sharing services. The ethical rationale for egg sharing is described: reducing the number of women exposed to the risks of stimulation and retrieval. This advantage is absent in sperm sharing where donation has no physical drawbacks. The key adverse social and emotional outcome of gamete sharing arises when the sharer’s own treatment is unsuccessful and the recipient’s is successful. This outcome is more likely in sperm sharing than in egg sharing given sperm from sharers can be used by up to 10 families whereas shared eggs only go to one other family.Given its morally relevant differences from egg sharing, sperm sharing requires its own ethical analysis. The HFEA should begin recording sperm sharing arrangements in order to enable meaningful ethical and policy scrutiny.
Hypospadias in toddlers: a multivariable study of prognostic factors in distal to mid-shaft hypospadias and review of literature
Authors: Roshandel M Reza , Aghaei Badr Tannaz , Kazemi Rashed Fahimeh , Salomon Samantha , Ghahestani Seyyed Mohammad , Ferrer Fernando A 
Published: January 2022

BackgroundTubularized incised plate urethroplasty is the most common hypospadias repair technique. However, there are unanswered questions and debates about the anatomical prognostic factors affecting the repair outcomes. This study tried to address some of the problems in the studies compromising the results of the current body of literature.MethodsA prospective cohort of 101 males aged 1–3 years undergoing primary distal to mid-shaft hypospadias repair were enrolled in the study. Complications including edema, erection, inadvertent removal of the urethral stent, surgical wound infection, bladder spasm, hematoma, and hemorrhage were evaluated. Studies in the current literature were reviewed to achieve a better perspective for future investigations.ResultsPersistent complications were found in 16 cases (15.8%) including fistula formation, the persistence of chordee, meatal stenosis, glans, and urethral dehiscence. The mean follow-up time was 6.6±3.4 months. In the single-variable analysis, the meatal location, the length and width of the urethral plate, and the reversible acute postoperative events were significantly associated with the complications. Furthermore, fistula formation was associated with acute surgical site infection (p<0.001). However, the multivariable regression study revealed the presurgical meatal location to be the only statistically significant factor (p=0.03). Notably, the glans diameter or glanular groove shape, urethral plate dimensions, or presence of mild chordee were not independently associated with the outcomes (p>0.05).ConclusionsOur study on the toddlers with hypospadias surgery revealed that the location of urethral meatal was the main predicting factor in the development of major complications. Furthermore, the fistula formation at the infected surgical site emphasizes the importance of postsurgical care.
Prenatal administration of heparin-binding epidermal growth factor-like growth factor in an experimental model of necrotizing enterocolitis decreased both incidence and severity of the disease
Authors: Sacks Marla Ashley , Mendez Yomara Stephanie , Khan Faraz A , Propst Robert , Zuppan Craig W , Wilson Christopher G , Radulescu Andrei 
Published: January 2022

BackgroundNecrotizing enterocolitis (NEC) is the leading gastrointestinal cause of death in premature infants and causes long-term disabilities. Previously, enteral heparin-binding epidermal growth factor-like growth factor (HB-EGF) administered after birth demonstrated decreased incidence and severity of NEC in a neonatal animal model of NEC. We investigated the potential prophylactic strategy of preventing NEC using prenatally administered HB-EGF.MethodsAn HB-EGF (800 µg/kg/dose) dose was injected into pregnant rats via tail vein or intraperitoneal route 2 hours prior to delivery. After cesarean section (C-section) at 21 days’ gestation, the rat pups were subjected to the NEC protocol by inducing stressors: hypoxia, hypothermia, hypertonic feeds, and orogastric gavage of lipopolysaccharide (2 mg/kg). Postnatally, pups were monitored for 96 hours and assessed for the development of clinical and postmortem histological NEC.ResultsThe experimental NEC incidence in untreated, stressed rat pups was 66%. Compared with untreated pups, the maternal administration of HB-EGF correlated with a significant NEC incidence and severity decrease in rat pups. The strongest decrease was seen when HB-EGF was administered via the intraperitoneal route 2 hours prior to C-section (66% vs 31%, *p<0.05). Prenatal HB-EGF administration significantly increased pups’ survival after NEC protocol exposure, with the greatest benefit observed in the group that received HB-EGF intraperitoneally 2 hours before delivery.ConclusionsPrenatal administration of HB-EGF decreases the incidence and severity of NEC, preserves gut barrier function and increases survival. This may represent a novel prophylactic clinical strategy for NEC offered to mothers at risk of delivering a premature infant.
Effect of soya phosphatidylcholine and possible underlying mechanism on ischemia/reperfusion injury in isolated perfused rat heart: an experimental and computational study
Authors: Mehta Anita A. , Patel Purav , Thakur Vandana R. , Beladiya Jayesh V. 
Published: January 2022

This study was designed to assess the effect of soya phosphatidylcholine (SPC) against ischemia/reperfusion (I/R) injury and the possible underlying mechanism using experimental and computational studies. I/R injury was induced by global ischemia for 30 min followed by reperfusion for 120 min. The perfusion of the SPC was performed for 10 min before inducing global ischemia. In the mechanistic study, the involvement of specific cellular pathways was identified using various inhibitors such as ATP-dependent potassium channel (KATP) inhibitor (glibenclamide), protein kinase C (PKC) inhibitor (chelerythrine), non-selective nitric oxide synthase inhibitor (L-NAME), and endothelium remover (Triton X-100). The computational study of various ligands was performed on toll-like receptor 4 (TLR4) protein using AutoDock version 4.0. SPC (100 μM) significantly decreased the levels of cardiac damage markers and %infarction compared with the vehicle control (VC). Furthermore, cardiodynamics (indices of left ventricular contraction (dp/dtmax), indices of left ventricular relaxation (dp/dtmin), coronary flow, and antioxidant enzyme levels were significantly improved as compared with VC. This protective effect was attenuated by glibenclamide, chelerythrine, and Triton X-100, but it was not attenuated by L-NAME. The computational study showed a significant bonding affinity of SPC to the TLR4-MD2 complex. Thus, SPC reduced myocardial I/R injury in isolated perfused rat hearts, which might be governed by the KATP channel, PKC, endothelium response, and TLR4-MyD88 signaling pathway.
Noble Design for Highly Active and Stable PEM Electrocatalyst Using Synergistic Interaction between Pt, TiO2 and Carbons
Authors: Ji Yunseong , Jeon Yukwon , Cho Yongil , Lee Chan Min , Hwang Ho Jung , Jeon Oksung , Kwon Oh Chan , Kim Jeong Pil , Shul Yong Gun 
Published: January 2022

As interest in climate change has increased in recent years, research on alternative energy sources is becoming more active. Fuel cells are one of the most promising electrochemical energy conversion devices that hold many advantages. In particular, polymer electrolyte fuel cells (PEMFCs) are attracting much attention due to their high power density and relatively good portability. In PEMFC systems, the main cost is due to the catalyst in terms of high cost of platinum group metals. This derives the need to understand the way how to get a highly active and stable electrocatalysts.
In general, Pt/C is most widely used catalyst because it has a large surface area for platinum anchoring, high electrical conductivity, and suitable pore structure for transferring reactant and product. However, carbon support undergoes carbon corrosion which is happened thermodynamically favored in fuel cell operation conditions. This phenomenon occurs at the surface of the carbon and it makes void places under the Pt nanoparticles. This mechanism causes losing electrochemical active sites. And there are also agglomeration and sintering of Pt particles on the carbon surface. Consequentially, carbon corrosion and platinum dissolution result in reduced electrochemical surface area (ECSA) and interferes long-term operations. Thus, electrochemically stable support materials need to be developed.
In various alternative material candidates, our group selected the TiO2 based support because it exhibits excellent chemical stability under severe acidic condition and offers the opportunity to modifying electronic structure of platinum particles. However, hindrances such as low electrical conductivity, catalytic activity, and surface area limit the direct use of TiO2 as a catalyst support. To remedy these drawbacks, we have designed carbon-titania composite support based electrocatalysts. These noble TiO2 – carbon hybrid support was synthesized from electrospun nanofibers and platinum nanoparticles are deposited on a support by microwave-assisted polyol process. Through our new approaches, we can obtain the electrocatalysts which have a unique 3D pore structure with higher surface area, modified electronic structure with increased intrinsic activity and extended cyclic durability.
Shining Light on the Nervous System: From Biomaterials to Bioelectronics
Authors: Tang Jing 
Published: January 2022

The dichotomy between advanced materials and brain has driven the curiosity of scientists to explore the wonders of the brain, as well as motivated the continued innovations of novel technologies based on advances in materials science and engineering to understand the brain. To improve treatments of brain-related diseases will require new tools and methods to map and to repair the brain with precision and biocompatibility. Current treatments of pain heavily rely on opioids, resulting in significant side effects such as addiction, tolerance, leading to the Opioid Overdose Crisis as we know of today. Smart drug delivery systems may provide an effective solution. Here I present the development of polymer-based externally-triggerable drug delivery systems for on-demand, repeatable and adjustable local anesthesia, where the timing, duration, and intensity of nerve block can be controlled through external energy triggers such as light. In addition to the new pharmacological approaches, bioelectronic platforms to enhance our insights into the eye and will also be discussed.
The restoration of light response with complex spatiotemporal features in retinal degenerative diseases towards retinal prosthesis has proven to be a considerable challenge over the past decades. Herein, inspired by the structure and function of photoreceptors in retinas, I develop artificial retina based on gold nanoparticle-decorated titania nanowire arrays, for restoration of visual responses in the blind mice with degenerated photoreceptors. Green, blue and near UV light responses in the retinal ganglion cells (RGCs) are restored with a spatial resolution better than 100 µm. ON responses in RGCs are blocked by glutamatergic antagonists, suggesting functional preservation of the remaining retinal circuits. Moreover, neurons in the primary visual cortex respond to light after subretinal implant of nanowire arrays. Improvement in pupillary light reflex suggests the behavioral recovery of light sensitivity. My study will shed light on the development of a new generation of optoelectronic toolkits for subretinal prosthetic devices. Through pharmacological, optical, and electrical toolsets, I aim to develop effective therapeutic solutions to neurological disease states. These results, along with a discussion of future neural interfaces, aim to improve our understanding of the nervous system and to inform new therapeutic approaches for biomaterials and bioelectronics.
Uveal Melanoma Exosomes Induce a Prometastatic Microenvironment through Macrophage Migration Inhibitory Factor
Authors: Ambrosini Grazia , Rai Alex J. , Carvajal Richard D. , Schwartz Gary K. 
Published: January 2022

Abstract

Uveal melanoma is a rare melanoma subtype different from cutaneous melanoma, with high incidence of liver metastasis and poor prognosis. Cancer cell–derived extracellular vesicles have been shown to induce proinflammatory and prometastatic signaling in the tumor microenvironment and at distant sites. The characterization of uveal melanoma exosome cargo and its role in metastatic spread is essential to identify targets and intervene in the early stages of metastatic development. Our study characterizes the proteomic content of uveal melanoma exosomes and identified the presence of markers with metastatic properties. We demonstrated that uveal melanoma exosomes induce activation of cell signaling pathways and the release of cytokines and growth factors from hepatocytes. These exosome-stimulated liver cells could in turn induce migration of uveal melanoma cells, confirming that the exosomes have a functional role in the cross-talk between these two cell types. We found that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) was a major player in these mechanisms and its blockade inhibited cell migration in coculture with exosome-stimulated hepatocytes and prevented the development of metastases in vivo. Targeting MIF in the early stages of metastasis may represent a novel adjuvant drug therapy to prevent metastatic spread in uveal melanoma.

Implications:
This study provides the first in vivo evidence that MIF inhibition may serve as a novel adjuvant drug therapy to prevent metastasis in uveal melanoma.
COX-2 Inhibitors Decrease Expression of PD-L1 in Colon Tumors and Increase the Influx of Type I Tumor-infiltrating Lymphocytes
Authors: Cecil Denise L. , Gad Ekram A. , Corulli Lauren R. , Drovetto Nicholas , Lubet Ronald A. , Disis Mary L. 
Published: January 2022

Abstract

Colon cancer is initiated under inflammatory conditions associated with upregulation of immune checkpoint proteins. We evaluated immune modulation induced by nonsteroidal anti-inflammatory agents used for colon cancer prevention. Both celecoxib and naproxen inhibited polyp growth in APC Min mice. Treatment of mice with either drug significantly decreased PD-L1 expression on polyps in a dose-dependent manner (P &lt; 0.0001 for both). The decrease in PD-L1 was associated with an influx of CD8+ T cells into polyps (P &lt; 0.0001, celecoxib; P = 0.048, naproxen) compared with lesions from untreated animals and correlated with disease control. Naproxen is a nonselective inhibitor of both COX-1 and COX-2, and we questioned the role of the different cyclooxygenases in PD-L1 regulation. Silencing either COX-2 or COX-1 RNA in the murine colon cancer cell line MC38, reduced PD-L1 expression by 86% in COX-2–silenced cells (P &lt; 0.0001) while there was little effect with COX-1 siRNA compared with control. Naproxen could inhibit the growth of MC38 in vivo. Naproxen-treated mice demonstrated a significant reduction in MC38 growth as compared with control (P &lt; 0001). Both Tbet+ CD4 and CD8 tumor-infiltrating lymphocytes (TIL) were significantly increased (P = 0.04 and P = 0.038, respectively) without a concurrent increase in GATA3+ TIL (P &gt; 0.05). CD8+ TIL highly expressed the activation marker, CD69. Not only was PD-L1 expression decreased on tumors, but LAG3+CD8+ T cells and PD-1 and LAG3 expression on regulatory T cells was also reduced (P = 0.008 and P = 0.002, respectively). These data demonstrate COX-2 inhibitors significantly decrease PD-L1 in colonic lesions and favorably impact the phenotype of tumor-infiltrating lymphocytes to control tumor growth.

Prevention Relevance:
Nonsteroidal anti-inflammatories (NSAID) are an essential component of any combination chemoprevention of colon cancer. We show NSAID treatment reduces PD-L1 expression on intestinal tumor cells. NSAID regulation of PD-L1 is dependent on COX-2 expression. These data underscore an important immunologic mechanism of action for NSAID in colon cancer prevention.
Watch the interview with Denise Cecil, PhD, recipient of the 2024 Cancer Prevention Research Award for Outstanding Journal Article: https://vimeo.com/992981665
See related Spotlight, p. 209
CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Preestablished Immunity
Authors: Shree Tanaya , Shankar Vishnu , Lohmeyer Julian J.K. , Czerwinski Debra K. , Schroers-Martin Joseph G. , Rodriguez Gladys M. , Beygi Sara , Kanegai Alyssa M. , Corbelli Karen S. , Gabriel Etelka , Kurtz David M. , Khodadoust Michael S. , Gupta Neel K. , Maeda Lauren S. , Advani Ranjana H. , Alizadeh Ash A. , Levy Ronald 
Published: January 2022

Abstract

To obtain a deeper understanding of poor responses to COVID-19 vaccination in patients with lymphoma, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies postvaccination, compared with 100% of controls. When evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.

Significance:
In a large cohort of patients with B-cell lymphoma, time since anti-CD20 treatment was an independent predictor of neutralizing antibody response to COVID-19 vaccination. Comparing patients who received anti-CD20 treatment before or after vaccination, we demonstrate that vaccinating first can generate an antibody response that endures through anti-CD20–containing treatment.
This article is highlighted in the In This Issue feature, p. 85
From Crisis Management to Realignment of Forces
Authors: Tagirova Alsu 
Published: January 2022

Abstract
In 1969, after a series of large-scale border clashes, the People's Republic of China (PRC) and the Soviet Union finally decided to enter negotiations to prevent a wider military confrontation. The de-escalation process that ensued gave Soviet and Chinese leaders two options: either to compromise and reach a settlement or to go back to a strategy of delay. This article shows that the choice between the two options depended on whether either state believed it could improve its relative position in a better political environment or could gain certain political advantage by immediately settling the dispute. Ultimately, both sides chose to return to a strategy of delay. The Chinese decision was influenced by the strategic configuration of U.S. “triangular” diplomacy and the hope that it would enhance the PRC's relative position. For Soviet officials, the outcome stemmed from a lack of trust in their Chinese counterparts.
“You Don't Know Khrushchev Well”
Authors: Torigian Joseph 
Published: January 2022

Abstract
The ouster of Nikita Khrushchev in October 1964 was a key moment in the history of elite politics in one of the most important authoritarian regimes of the twentieth century. Yet political scientists and historians have long seemed uninterested in Khrushchev's downfall, regarding it as the largely “inevitable” result of his supposedly unpopular policies. Archival sources that have recently come to light cast serious doubt on this assessment and demonstrate new ways of measuring contingency. By showing the countermeasures Khrushchev could have taken, the importance of timing, and the sense among the plotters that their move was highly risky, this article demonstrates that Khrushchev's defeat was far from preordained. The lesson of October 1964 is not that policy differences or failures lead inexorably to political defeat, but that elite politics in Marxist-Leninist regimes is inherently ambiguous, personal, and, most importantly, highly contingent.