bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab-based induction chemoimmunotherapy and PD-L1 expression in locoregionally advanced HPV-associated oropharyngeal squamous cell carcinoma.
Authors: Rosenberg Ari , Pearson Alexander T. , Agrawal Nishant , Juloori Aditya , Seiwert Tanguy Y. , Gooi Zhen , Blair Elizabeth A. , Izumchenko Evgeny , Chin Jeffrey , Ginat Daniel , Lingen Mark , Haraf Daniel J. , Vokes Everett E. 
Published: June 2022

6075 Background: Blockade of the PD-1/PD-L1 immune checkpoint improves survival in recurrent/metastatic head and neck cancer. PD-L1 expression is a biomarker that enriches for clinical benefit with anti-PD-1 therapy alone or in combination with chemotherapy in this setting. The role of PD-L1 expression as a predictive biomarker in locoregional human papillomavirus associated (HPV+) head and neck cancer (HNC) treated with induction nivolumab-based chemoimmunotherapy is unknown. We evaluate PD-L1 expression and response to induction chemoimmunotherapy in the context of an investigator initiated trial, OPTIMA II. Methods: Patients with locoregionally advanced HPV+ HNC were enrolled to the prospective OPTIMA II study evaluating induction chemoimmunotherapy followed by response adaptive de-escalated locoregional therapy. Induction therapy consisted of nivolumab, nab-paclitaxel, and carboplatin, for three cycles. Anatomic imaging of the head and neck with either CT or MRI was obtained at baseline and following induction therapy. Expression of PD-L1 was assessed by immunohistochemistry on baseline biopsies and calculation of tumor proportion score (TPS) and combined positive score (CPS) was performed. Response is defined as percentage of tumor shrinkage per RECIST 1.1 criteria. Deep response rate is defined as the proportion of patients with > = 50% tumor shrinkage. Kruskal-Wallis and Mann-Whitney tests were used for analysis. Results: Twenty-nine patients (pts) underwent evaluation of PD-L1 expression and started treatment with induction chemoimmunotherapy. Median age 61 (range 37-81), smoker > 20 pack years in 24%, tonsil primary in 79%, and HPV16 subtype in 97%. The median response following induction was 63% (range 29% to 100%). PD-L1 TPS scores were < 1, 1-19, and > = 20 in 28%, 34%, and 38% respectively. PD-L1 CPS scores were < 20 and > = 20 in 55% and 45% respectively. Median response among PD-L1 TPS of < 1, 1-19, and > = 20 was 49%, 59%, and 66% respectively (p = 0.16). Among PD-L1 CPS of < 20 and > = 20, median response was 57% and 69% respectively (p = 0.11). The deep response rate among PD-L1 CPS < 20 and > = 20 was 69% and 77% respectively. Conclusions: Deep responses were observed following induction chemoimmunotherapy in locoregionally advanced HPV+ HNC. There was a non-significant increase in median response and deep response rate with higher expression of PD-L1. Evaluation of PD-L1 expression as a biomarker for response with induction chemoimmunotherapy is worthy of further investigation in locoregional HPV+ disease. Clinical trial information: NCT03107182.
Circulating tumor DNA profiling and serial analysis in salivary gland carcinomas reveal unique mutational subsets and actionable alterations.
Authors: Russell Jeffery Scott , Kerrigan Kathleen Claire , Yang Dong 
Published: June 2022

6097 Background: Salivary gland carcinoma is a rare head and neck malignancy without any FDA approved treatment options. ctDNA profiling has been shown to be a valuable tool in identifying novel targets and expanding potential therapeutic options. Here, we report the landscape of ctDNA in a large dataset of salivary gland carcinomas. Methods: Analysis of genomic results from blood samples with a diagnosis of salivary gland carcinoma that were prospectively collected between January 2017 to December 2021 for clinical Guardant360 testing. Histologic subtype was documented by ordering providers as available. Serial tests were defined as having Guardant360 analysis performed on more than one sample collected at more than one timepoint. Results: Among 222 patients tested with Guardant360, 59.5% were male and the median age was 64 years (range 22-93 years). Of reported diagnoses, 137 (61.7%) patients had salivary gland carcinoma NOS. The remaining samples were designated by specific salivary histology: 13 (5.9%) salivary gland mucoepidermoid carcinoma (SGMC), 19 (8.6%) salivary gland adenocarcinoma (SGA), 37 (16.7%) salivary gland adenoid cystic carcinoma (SGACC), and 16 (72%) salivary duct carcinoma (SDC). ctDNA genomic alterations (GAs) were identified in 205 (81.3%) of 252 samples. The median variant allele fraction was 0.6% (range 0.01%-46.4%). TMB was evaluated in 45 samples of which 33 were evaluable and the median and 80th percentile of TMB was 8.44 and 11.81 mut/Mb. MSI-H was not detected in any of the 181 samples tested for MSI. The most commonly altered genes were TP53, PIK3CA, ERBB2, ATM, EGFR and HRAS across all collected salivary samples. Further analysis stratified genetic alterations by tissue subtype. Other than TP53, common mutations by salivary gland carcinoma subtype included: PI3KCA (SGACC/SDC), ERBB2 (SGA), and EGFR (SGMC). In regards to serial analysis, 16 patients had at least 2 serial tests. When comparing the subsequent testing within the same patient, 3 patients had potentially new actionable GAs (including BRAF, KRAS mutations and EGFR amplification) on the subsequent test that were not identified on the original test. Conclusions: Blood-based liquid biopsy can be applied in salivary gland tumors to detect genomic alterations in ctDNA which may provide opportunities for therapeutic intervention in a cancer with limited treatment options. Additionally, ctDNA testing may be used to identify resistant alterations to potential therapy. Finally, longitudinal assessment of ctDNA may shed light on tumor evolution and additional therapeutic targets may be found. Further assessment of serial ctDNA analysis and the potential impact on patient clinical outcomes needs to be elucidated.
Variants of SLC2A10 may be Linked to Poor Response to Metformin
Authors: Paz-Pacheco Elizabeth , Nevado Jose B , Cutiongco-de la Paz Eva Maria C , Jasul Gabriel V , Aman Aimee Yvonne Criselle L , Ribaya Elizabeth Laurize A , Francisco Mark David G , Guanzon Ma Luz Vicenta V , Uyking-Naranjo May L , Añonuevo-Cruz Ma Cecille S , Maningat Maria Patricia Deanna D , Jaring Cristina V , Nacpil-Dominguez Paulette D , Pala-Mohamad Aniza B , Canto Abigail U , Quisumbing John Paul M , Lat Annabelle Marie M , Bernardo Diane Carla C , Mansibang Noemie Marie M , Calpito Karell Jo Angelique C , Ribaya Vincent Sean D , Ferrer Julius Patrick Y , Biwang Jessica H , Melegrito Jodelyn B , Deguit Christian Deo T , Panerio Carlos Emmanuel G 
Published: June 2022

Abstract

Purpose
A study among Filipinos revealed that only 15% of patients with diabetes achieved glycemic control, and poor response to metformin could be one of the possible reasons. Recent studies demonstrate how genetic variations influence response to metformin. Hence, the present study aimed to determine genetic variants associated with poor response to metformin.

Methods
Using a candidate variant approach, 195 adult Filipino participants with newly diagnosed type 2 diabetes mellitus (T2DM) were enrolled in a case-control study. Genomic DNA from blood samples were collected. Allelic and genotypic associations of variants with poor response to metformin were determined using exact statistical methods.

Results
Several polymorphisms were nominally associated with poor response to metformin (Puncorr &lt; 0.05). The most notable is the association of multiple variants in the SLC2A10 gene—rs2425911, rs3092412, and rs2425904—with common additive genetic mode of inheritance. Other variants that have possible associations with poor drug response include rs340874 (PROX-AS1), rs815815 (CALM2), rs1333049 (CDKN2B-AS1), rs2010963 (VEGFA), rs1535435 and rs9494266 (AHI1), rs11128347 (PDZRN3), rs1805081 (NPC1), and rs13266634 (SLC30A8).

Conclusion
In Filipinos, a trend for the association for several variants was noted, with further observation that several mechanisms may be involved. The results may serve as pilot data for further validation of candidate variants for T2DM pharmacotherapy.
Investigating the Effect of Estradiol Levels on the Risk of Breast, Endometrial, and Ovarian Cancer
Authors: Johansson Åsa , Schmitz Daniel , Höglund Julia , Hadizadeh Fatemeh , Karlsson Torgny , Ek Weronica E 
Published: June 2022

Abstract

Background
High levels of estrogen are associated with increased risk of breast and endometrial cancer and have been suggested to also play a role in the development of ovarian cancer. Cancerogenic effects of estradiol, the most prominent form of estrogen, have been highlighted as a side effect of estrogen-only menopausal hormone therapy. However, whether high levels of endogenous estrogens, produced within the body, promote cancer development, has not been fully established.

Objective
We aimed to examine causal effects of estradiol on breast, endometrial, and ovarian cancer.

Methods
Here we performed a two-sample Mendelian randomization (MR) to estimate the effect of endogenous estradiol on the risk of developing breast, endometrial, and ovarian cancer, using the UK Biobank as well as 3 independent cancer cohorts.

Results
Using 3 independent instrumental variables, we showed that higher estradiol levels significantly increase the risk for ovarian cancer (OR = 3.18 [95% CI, 1.47-6.87], P = 0.003). We also identified a nominally significant effect for ER-positive breast cancer (OR = 2.16 [95% CI, 1.09-4.26], P = 0.027). However, we could not establish a clear link to the risk of endometrial cancer (OR = 1.93 [95% CI, 0.77-4.80], P = 0.160).

Conclusion
Our results suggest that high estradiol levels promote the development of ovarian and ER-positive breast cancer.
Severe Cholestatic Jaundice (Stauffer Syndrome) as a Rare Paraneoplastic Manifestation in Adrenocortical Carcinoma
Authors: Murvelashvili Natia , Polanco Patricio M , Khorsand Sarah M , Marrero Jorge A , Jia Liwei , Mirfakhraee Sasan , Else Tobias , Habra Mouhammed Amir , Cole Suzanne , Hamidi Oksana 
Published: June 2022

Abstract

Background
Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. While ACC can be associated with adrenal hormone excess syndromes, classic paraneoplastic syndromes are rarely seen. Stauffer syndrome, a paraneoplastic phenomenon characterized by reversible cholestasis in the absence of liver metastases, has been described with renal carcinoma and other malignancies but has not been previously reported in ACC.

Case Presentation
A 38-year-old man presented with emesis, painless jaundice, pruritus, and weight loss. Laboratory evaluation demonstrated elevated total bilirubin of 8.7 mg/dL (N &lt; 1.3 mg/dL). Computed tomography revealed a 20.4-cm left adrenal mass without evidence of liver metastases. The patient’s condition deteriorated rapidly with progressive renal failure and worsening hyperbilirubinemia. The patient underwent left adrenalectomy, nephrectomy, ureterolysis, and wedge liver biopsy. Histopathology showed necrotic ACC with tumor invasion into the adrenal capsule, no lymphovascular invasion, uninvolved margins, and Ki-67 of 40%. Kidney parenchyma exhibited diffuse pigment casts. The liver specimen contained diffuse bile deposits and minimal chronic inflammation in the portal tracts. He tested positive for the pathogenic variant of folliculin (FLCN) gene consistent with Birt-Hogg-Dube syndrome. Renal function recovered after surgery, and bilirubin level normalized after several weeks. Based on clinical presentation and absence of other etiologies, reversible cholestatic jaundice was attributed to Stauffer syndrome.

Conclusion
This is the first report of a unique presentation of paraneoplastic-related hyperbilirubinemia in the setting of ACC. While extremely rare, Stauffer syndrome should still be considered in differential diagnosis in patients with ACC with liver dysfunction and jaundice without evidence of liver metastases.
Involvement of the liver-gut peripheral neural axis in nonalcoholic fatty liver disease pathologies via hepatic HTR2A
Authors: Owaki Takashi , Kamimura Kenya , Ko Masayoshi , Nagayama Itsuo , Nagoya Takuro , Shibata Osamu , Oda Chiyumi , Morita Shinichi , Kimura Atsushi , Sato Takeki , Setsu Toru , Sakamaki Akira , Kamimura Hiroteru , Yokoo Takeshi , Terai Shuji 
Published: June 2022

ABSTRACT
Serotonin (5-HT) is one of the key bioamines of nonalcoholic fatty liver disease (NAFLD). Its mechanism of action in autonomic neural signal pathways remains unexplained; hence, we evaluated the involvement of 5-HT and related signaling pathways via autonomic nerves in NAFLD. Diet-induced NAFLD animal models were developed using wild-type and melanocortin 4 receptor (MC4R) knockout (MC4RKO) mice, and the effects of the autonomic neural axis on NAFLD physiology, 5-HT and its receptors (HTRs), and lipid metabolism-related genes were assessed by applying hepatic nerve blockade. Hepatic neural blockade retarded the progression of NAFLD by reducing 5-HT in the small intestine, hepatic HTR2A and hepatic lipogenic gene expression, and treatment with an HTR2A antagonist reproduced these effects. The effects were milder in MC4RKO mice, and brain 5-HT and HTR2C expression did not correlate with peripheral neural blockade. Our study demonstrates that the autonomic liver-gut neural axis is involved in the etiology of diet-induced NAFLD and that 5-HT and HTR2A are key factors, implying that the modulation of the axis and use of HTR2A antagonists are potentially novel therapeutic strategies for NAFLD treatment.
This article has an associated First Person interview with the first author of the paper.
Comparative analysis of young people's ideas about the image of employees of the internal affairs bodies of the Russian Federation
Authors: Kutyepova Marina , Ivanova Regina 
Published: June 2022

The article presents the results of studying the public opinion of young people about the image of an employee of the internal affairs bodies of the Russian Federation, which is an important component in the work to correct the prevailing negative stereotypes and form a positive image of the Russian police.
Since the opinion of representatives of such an important part of Russian society as youth should be studied and taken into account to determine the directions of this work, during the study, using the method of non-standardized survey, an analysis of young people's ideas about the image of an employee of the internal affairs bodies of the Russian Federation was carried out, 52 cadets of the educational organization of the Ministry of Internal Affairs of Russia and 52 students of higher educational institutions of the Russian Federation were interviewed to solve this problem. Moscow.
The results of the study indicate that the cadets of the educational organization of the Ministry of Internal Affairs of Russia and university students have a significantly different attitude towards the police, if most of the cadets noted a positive attitude, then the students showed a negative or neutral attitude towards the internal affairs bodies of the Russian Federation. Therefore, the task of increasing the authority of the police and trust in it among young people is paramount.
Machine Learning vs. Economic Restrictions: Evidence from Stock Return Predictability
Authors: Avramov Doron , Cheng Si , Metzker Lior 
Published: June 2022

This paper shows that investments based on deep learning signals extract profitability from difficult-to-arbitrage stocks and during high limits-to-arbitrage market states. In particular, excluding microcaps, distressed stocks, or episodes of high market volatility considerably attenuates profitability. Machine learning-based performance further deteriorates in the presence of reasonable trading costs because of high turnover and extreme positions in the tangency portfolio implied by the pricing kernel. Despite their opaque nature, machine learning methods successfully identify mispriced stocks consistent with most anomalies. Beyond economic restrictions, deep learning signals are profitable in long positions and recent years and command low downside risk. This paper was accepted by Kay Giesecke, finance. Funding: D. Avramov acknowledges the Israel Science Foundation (Grant 288/18) for financial support. S. Cheng acknowledges the General Research Fund of the Research Grants Council of Hong Kong [Project 14502318] for financial support. Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2022.4449 .
Pandora’s Box Problem with Order Constraints
Authors: Boodaghians Shant , Fusco Federico , Lazos Philip , Leonardi Stefano 
Published: June 2022

The Pandora’s Box problem, originally posed by Weitzman in 1979, models selection from a set of random-valued alternatives—the “boxes”—when evaluation is costly. Weitzman showed that the Pandora’s Box problem admits a simple threshold-based solution that considers the options in decreasing order of reservation value, a proxy for the actual value of the boxes in the exploration process. We study for the first time this problem when the order in which the boxes are opened is constrained, forcing the solution to account for both the depth of search, as opening a box gives access to more boxes, and the breadth, as there are many directions to explore. Despite these difficulties, we show that greedy optimal strategies exist and can be efficiently computed for tree-like order constraints. We also prove that finding optimal adaptive search strategies is NP-hard to approximate (up to a certain constant) when certain matroid constraints are applied to further restrict the set of boxes that may be opened or when the order constraints are given as reachability constraints on a directed acyclic graph. We complement this hardness result by giving efficient approximation algorithms, exploiting a low adaptivity gap for a carefully relaxed version of the problem. Funding: This work was supported by the National Science Foundation [Grant 1750436] and the Ministero dell'Istruzione, dell'Università e della Ricerca [PRIN. ALGADIMAR “Algorithms, Games, and Digital]. This work was also supported by the ERC Advanced [Grant 788893] Algorithmic and Mechanism Design Research in Online Markets (AMDROMA).
Uveitis prior to clinical presentation of Multiple Sclerosis (MS) is associated with better MS prognosis
Authors: Raskin Eyal , Achiron Anat , Zloto Ofira , Neuman Ron , Vishnevskia-Dai Vicktoria 
Published: June 2022

Objective
An association between uveitis and multiple sclerosis (MS) is well-established, but the actual nature of that association remains poorly understood. We sought to determine the association between the presence of a uveitis diagnosis prior to an MS diagnosis compared to no pre-existing uveitis diagnosis in MS patients.

Methods
Patients in whom the presentation of uveitis preceded the presentation of MS (study group) and patients with MS and no uveitis (control group) were randomly selected at a ratio of 1:3 from the Sheba Multiple Sclerosis Center computerized database.

Results
Eleven patients presented with uveitis prior to MS diagnosis (study group), and 31 randomly selected patients had MS without uveitis (control group). Only one patient in the study group deteriorated to EDSS 3 during the follow-up period, compared to 15 patients in the control group (9.1% vs 48.4%, P = 0.049). None of the patients in the study group reached EDSS 6 during the 10 years of follow-up compared to 6 (19.4%) patients in the control group (P = 0.194).

Conclusions
MS patients who presented with uveitis that preceded their neurological symptoms of MS demonstrated a clinically significant better neurological prognosis, than our MS patients with no uveitis.
A systematic review and meta-analysis on impact of suboptimal use of antidepressants, bisphosphonates, and statins on healthcare resource utilisation and healthcare cost
Authors: Park Kyu Hyung , Tickle Leonie , Cutler Henry 
Published: June 2022

Background
Depression, osteoporosis, and cardiovascular disease impose a heavy economic burden on society. Understanding economic impacts of suboptimal use of medication due to nonadherence and non-persistence (non-MAP) for these conditions is important for clinical practice and health policy-making.

Objective
This systematic literature review aims to assess the impact of non-MAP to antidepressants, bisphosphonates and statins on healthcare resource utilisation and healthcare cost (HRUHC), and to assess how these impacts differ across medication classes.

Methods
A systematic literature review and an aggregate meta-analysis were performed. Using the search protocol developed, PubMed, Cochrane Library, ClinicalTrials.gov, JSTOR and EconLit were searched for articles that explored the relationship between non-MAP and HRUHC (i.e., use of hospital, visit to healthcare service providers other than hospital, and healthcare cost components including medical cost and pharmacy cost) published from November 2004 to April 2021. Inverse-variance meta-analysis was used to assess the relationship between non-MAP and HRUHC when reported for at least two different populations.

Results
Screening 1,123 articles left 10, seven and 13 articles on antidepressants, bisphosphonates, and statins, respectively. Of those, 27 were rated of good quality, three fair and none poor using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. In general, non-MAP was positively associated with HRUHC for all three medication classes and most prominently for bisphosphonates, although the relationships differed across HRUHC components and medication classes. The meta-analysis found that non-MAP was associated with increased hospital cost (26%, p = 0.02), outpatient cost (10%, p = 0.01), and total medical cost excluding pharmacy cost (12%, p<0.00001) for antidepressants, and increased total healthcare cost (3%, p = 0.07) for bisphosphonates.

Conclusions
This systematic literature review is the first to compare the impact of non-MAP on HRUHC across medications for three prevalent conditions, depression, osteoporosis and cardiovascular disease. Positive relationships between non-MAP and HRUHC highlight inefficiencies within the healthcare system related to non-MAP, suggesting a need to reduce non-MAP in a cost-effective way.