bluuebunny/crossref_metadata_2025_split huggingface dataset:
Strategy to Reduce Floor Area and Flow Distance of Products in Multi-Row Parallel Machine Layout Design Using Cuckoo Search Algorithm
Authors: Mahalingam Siva Kumar , Nagarajan Lenin 
Published: February 2021

A multi-row parallel machine layout (MRPML) design is the best alternative solution to overcome the downside associated with a single-row machine layout design. Especially, the reduction in the investment cost on machines by eliminating its duplicates is the greatest advantage of a MRPML over the single-row machine layout. This paper addresses the MRPML design strategy to reduce the floor area of the layout along with a reduction in demand-based flow distance of products. The cuckoo search algorithm is used for this purpose. The efficacy of the proposed method is assessed and proved by comparing the solutions to the problems associated with single-row layout design dealt by [Lenin et al. Eur. J. Ind. Eng. 12(2) (2018) 252–275] and multi-row layout design dealt by [Vitayasak and Pongcharoen Exp. Syst. Appl. 98 (2018) 129–152] along with few randomly generated problems. This work provides a better tool to identify the optimal MRPML design to satisfy the objectives of mass production industries.
Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex
Authors: Kovalenko Andrii , Sanin Andres , Kosmas Kosmas , Zhang Long , Wang Ji , Akl Elie W. , Giannikou Krinio , Probst Clemens K. , Hougard Thomas R. , Rue Ryan W. , Krymskaya Vera P. , Asara John M. , Lam Hilaire C. , Kwiatkowski David J. , Henske Elizabeth P. , Filippakis Harilaos 
Published: February 2021

Abstract

Lymphangioleiomyomatosis is a rare destructive lung disease affecting primarily women and is the primary lung manifestation of tuberous sclerosis complex (TSC). In lymphangioleiomyomatosis, biallelic loss of TSC1/2 leads to hyperactivation of mTORC1 and inhibition of autophagy. To determine how the metabolic vulnerabilities of TSC2-deficient cells can be targeted, we performed a high-throughput screen utilizing the “Repurposing” library at the Broad Institute of MIT and Harvard (Cambridge, MA), with or without the autophagy inhibitor chloroquine. Ritanserin, an inhibitor of diacylglycerol kinase alpha (DGKA), was identified as a selective inhibitor of proliferation of Tsc2−/− mouse embryonic fibroblasts (MEF), with no impact on Tsc2+/+ MEFs. DGKA is a lipid kinase that metabolizes diacylglycerol to phosphatidic acid, a key component of plasma membranes. Phosphatidic acid levels were increased 5-fold in Tsc2−/− MEFs compared with Tsc2+/+ MEFs, and treatment of Tsc2−/− MEFs with ritanserin led to depletion of phosphatidic acid as well as rewiring of phospholipid metabolism. Macropinocytosis is known to be upregulated in TSC2-deficient cells. Ritanserin decreased macropinocytic uptake of albumin, limited the number of lysosomes, and reduced lysosomal activity in Tsc2−/− MEFs. In a mouse model of TSC, ritanserin treatment decreased cyst frequency and volume, and in a mouse model of lymphangioleiomyomatosis, genetic downregulation of DGKA prevented alveolar destruction and airspace enlargement. Collectively, these data indicate that DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis and promote proliferation. Targeting macropinocytosis with ritanserin may represent a novel therapeutic approach for the treatment of TSC and lymphangioleiomyomatosis.

Significance:
This study identifies macropinocytosis and phospholipid metabolism as novel mechanisms of metabolic homeostasis in mTORC1-hyperactive cells and suggest ritanserin as a novel therapeutic strategy for use in mTORC1-hyperactive tumors, including pancreatic cancer.
Tumor-Derived Pericytes Driven by EGFR Mutations Govern the Vascular and Immune Microenvironment of Gliomas
Authors: Segura-Collar Berta , Garranzo-Asensio María , Herranz Beatriz , Hernández-SanMiguel Esther , Cejalvo Teresa , Casas Bárbara S. , Matheu Ander , Pérez-Núñez Ángel , Sepúlveda-Sánchez Juan Manuel , Hernández-Laín Aurelio , Palma Verónica , Gargini Ricardo , Sánchez-Gómez Pilar 
Published: February 2021

Abstract

The extraordinary plasticity of glioma cells allows them to contribute to different cellular compartments in tumor vessels, reinforcing the vascular architecture. It was recently revealed that targeting glioma-derived pericytes, which represent a big percentage of the mural cell population in aggressive tumors, increases the permeability of the vessels and improves the efficiency of chemotherapy. However, the molecular determinants of this transdifferentiation process have not been elucidated. Here we show that mutations in EGFR stimulate the capacity of glioma cells to function as pericytes in a BMX- (bone marrow and X-linked) and SOX9-dependent manner. Subsequent activation of platelet-derived growth factor receptor beta in the vessel walls of EGFR-mutant gliomas stabilized the vasculature and facilitated the recruitment of immune cells. These changes in the tumor microenvironment conferred a growth advantage to the tumors but also rendered them sensitive to pericyte-targeting molecules such as ibrutinib or sunitinib. In the absence of EGFR mutations, high-grade gliomas were enriched in blood vessels, but showed a highly disrupted blood–brain barrier due to the decreased BMX/SOX9 activation and pericyte coverage, which led to poor oxygenation, necrosis, and hypoxia. Overall, these findings identify EGFR mutations as key regulators of the glioma-to-pericyte transdifferentiation, highlighting the intricate relationship between the tumor cells and their vascular and immune milieu. Our results lay the foundations for a vascular-dependent stratification of gliomas and suggest different therapeutic vulnerabilities determined by the genetic status of EGFR.

Significance:
This study identifies the EGFR-related mechanisms that govern the capacity of glioma cells to transdifferentiate into pericytes, regulating the vascular and immune phenotypes of the tumors.
High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9
Authors: Majumder Shounak , Taylor William R. , Foote Patrick H. , Berger Calise K. , Wu Chung Wah , Mahoney Douglas W. , Bamlet William R. , Burger Kelli N. , Postier Neil , de la Fuente Jaime , Doering Karen A. , Lidgard Graham P. , Allawi Hatim T. , Petersen Gloria M. , Chari Suresh T. , Ahlquist David A. , Kisiel John B. 
Published: February 2021

AbstractPurpose:We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case–control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC.Experimental Design:Thirteen MDMs (GRIN2D, CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated.Results:The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89–0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87–0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98–1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76–0.92), CA19-9 alone was 0.87 (0.79–0.94), and combined MDM-CA19-9 panel was 0.90 (0.84–0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%–99%) for stage I disease and 82% (68%–92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86–0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84–0.93) versus 0.97 (0.94–0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%–98%), with an observed specificity of 92% at the preset specificity of 97.5%.Conclusions:Plasma MDMs in combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.
Immune-related Gene Expression Predicts Response to Neoadjuvant Chemotherapy but not Additional Benefit from PD-L1 Inhibition in Women with Early Triple-negative Breast Cancer
Authors: Sinn Bruno V. , Loibl Sibylle , Hanusch Claus A. , Zahm Dirk-Michael , Sinn Hans-Peter , Untch Michael , Weber Karsten , Karn Thomas , Becker Clemens , Marmé Frederik , Schmitt Wolfgang D. , Müller Volkmar , Schem Christian , Treue Denise , Stickeler Elmar , Klauschen Frederik , Burchardi Nicole , Furlanetto Jenny , van Mackelenbergh Marion , Fasching Peter A. , Schneeweiss Andreas , Denkert Carsten 
Published: February 2021

Abstract

Purpose:
We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer.

Experimental Design:
Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers.

Results:
Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130–2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234–2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling.

Conclusions:
Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.
KRAS
G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma
Authors: Jones Gregory D. , Caso Raul , Tan Kay See , Mastrogiacomo Brooke , Sanchez-Vega Francisco , Liu Yuan , Connolly James G. , Murciano-Goroff Yonina R. , Bott Matthew J. , Adusumilli Prasad S. , Molena Daniela , Rocco Gaetano , Rusch Valerie W. , Sihag Smita , Misale Sandra , Yaeger Rona , Drilon Alexander , Arbour Kathryn C. , Riely Gregory J. , Rosen Neal , Lito Piro , Zhang Haiying , Lyden David C. , Rudin Charles M. , Jones David R. , Li Bob T. , Isbell James M. 
Published: February 2021

Abstract

Purpose:
KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant lung adenocarcinoma.

Experimental Design:
Patients who underwent resection of stage I–III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed.

Results:
In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank P = 0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3–10.8) vs. 6.1 (3.5–9.7); P = 0.021], compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort.

Conclusions:
KRAS G12C mutations are associated with worse DFS after complete resection of stage I–III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.
Enhancing the Generation of Eomeshi CD8+ T Cells Augments the Efficacy of OX40- and CTLA-4–Targeted Immunotherapy
Authors: Emerson Dana A. , Rolig Annah S. , Redmond William L. 
Published: February 2021

Abstract
CTLA-4 blockade in combination with an agonist OX40-specific monoclonal antibody synergizes to augment antitumor immunity through enhanced T-cell effector function, leading to increased survival in preclinical cancer models. We have shown previously that anti-OX40/anti–CTLA-4 combination therapy synergistically enhances the expression of Eomesodermin (Eomes) in CD8+ T cells. Eomes is a critical transcription factor for the differentiation and memory function of CD8+ T cells. We hypothesized that EomeshiCD8+ T cells were necessary for anti-OX40/anti–CTLA-4 immunotherapy efficacy and that further enhancement of this population would improve tumor-free survival. Indeed, CD8+ T cell–specific deletion of Eomes abrogated the efficacy of anti-OX40/anti–CTLA-4 therapy. We also found that anti-OX40/anti–CTLA-4–induced EomeshiCD8+ T cells expressed lower levels of checkpoint receptors (PD1, Tim-3, and Lag-3) and higher levels of effector cytokines (IFNγ and TNFα) than their Eomeslo counterparts. Eomes expression is negatively regulated in T cells through interleukin-2–inducible T-cell kinase (ITK) signaling. We investigated the impact of modulating ITK signaling with ibrutinib, an FDA-approved tyrosine kinase inhibitor, and found that anti-OX40/anti–CTLA-4/ibrutinib therapy further enhanced CD8+ T cell–specific Eomes expression, leading to enhanced tumor regression and improved survival, both of which were associated with increased T-cell effector function across multiple tumor models. Taken together, these data demonstrate the potential of anti-OX40/anti–CTLA-4/ibrutinib as a triple therapy to improve the efficacy of immunotherapy.
Modifiable Cardiovascular Risk Factors in Patients With Sporadic Cerebral Cavernous Malformations
Authors: Chen Bixia , Saban Dino , Rauscher Steffen , Herten Annika , Rauschenbach Laurèl , Santos Alejandro , Li Yan , Schmidt Boerge , Zhu Yuan , Jabbarli Ramazan , Wrede Karsten H. , Kleinschnitz Christoph , Sure Ulrich , Dammann Philipp 
Published: February 2021

Background and Purpose:
This study aims to assess the influence of modifiable cardiovascular risk factors on hemorrhage risk of sporadic cerebral cavernous malformations (CCMs).

Methods:

From 1219 consecutive CCM patients (2003–2018), adult subjects with sporadic CCM and complete magnetic resonance imaging were included. We evaluated presence of intracerebral hemorrhage (ICH) as mode of presentation, occurrence of ICH during follow-up and risk factors arterial hypertension, diabetes, hyperlipidemia, nicotine abuse, and obesity (body mass index >30 kg/m
2
). Impact of risk factors on ICH at presentation was calculated using univariate and multivariate logistic regression with age and sex adjustment. We performed Kaplan-Meier and Cox regression to analyze cumulative 5-year risk for (re)bleeding.

Results:

We included 682 patients with CCM. The univariate logistic regression showed a significant relationship (odds ratio=1.938 [95% CI, 1.120–3.353],
P
=0.018) between obesity and ICH as mode of presentation. Multivariate adjusted logistic regression confirmed significant correlation with odds ratio=1.902 (95% CI, 1.024–3.532,
P
=0.042). Cox regression did not identify predictors for occurrence of (re)hemorrhage (
P
>0.05; hazard ratios: arterial hypertension 1.112 [95% CI, 0.622–1.990], diabetes 0.850 [95% CI, 0.208–3.482], hyperlipidemia 0.719 [95% CI, 0.261–1.981], nicotine abuse 1.123 [95% CI, 0.591–2.134], and obesity 0.928 [95% CI, 0.416–2.070]).

Conclusions:
This study provides evidence that obesity may be a risk factor for CCM hemorrhage. It was significantly associated with ICH as mode of presentation. Other risk factors (arterial hypertension, diabetes, hyperlipidemia, and current nicotine abuse) showed no such effect. None of the factors showed to be independent predictors for cumulative 5-year risk of (re)bleeding.
Automated Quantification of Reduced Sulcal Volume Identifies Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage
Authors: Yuan Jane Y. , Chen Yasheng , Kumar Atul , Zlepper Zach , Jayaraman Keshav , Aung Wint Y. , Clarke Julian V. , Allen Michelle , Athiraman Umeshkumar , Osbun Joshua , Zipfel Gregory J. , Dhar Rajat 
Published: February 2021

Background and Purpose:
Early brain injury may be a more significant contributor to poor outcome after aneurysmal subarachnoid hemorrhage (aSAH) than vasospasm and delayed cerebral ischemia. However, studying this process has been hampered by lack of a means of quantifying the spectrum of injury. Global cerebral edema (GCE) is the most widely accepted manifestation of early brain injury but is currently assessed only through subjective, qualitative or semi-quantitative means. Selective sulcal volume (SSV), the CSF volume above the lateral ventricles, has been proposed as a quantitative biomarker of GCE, but is time-consuming to measure manually. Here we implement an automated algorithm to extract SSV and evaluate the age-dependent relationship of reduced SSV on early outcomes after aSAH.

Methods:
We selected all adults with aSAH admitted to a single institution with imaging within 72 hours of ictus. Scans were assessed for qualitative presence of GCE. SSV was automatically segmented from serial CTs using a deep learning-based approach. Early SSV was the lowest SSV from all early scans. Modified Rankin Scale score of 4 to 6 at hospital discharge was classified as a poor outcome.

Results:
Two hundred forty-four patients with aSAH were included. Sixty-five (27%) had GCE on admission while 24 developed it subsequently within 72 hours. Median SSV on admission was 10.7 mL but frequently decreased, with minimum early SSV being 3.0 mL (interquartile range, 0.3–11.9). Early SSV below 5 mL was highly predictive of qualitative GCE (area under receiver-operating-characteristic curve, 0.90). Reduced early SSV was an independent predictor of poor outcome, with a stronger effect in younger patients.

Conclusions:
Automated assessment of SSV provides an objective biomarker of GCE that can be leveraged to quantify early brain injury and dissect its impact on outcomes after aSAH. Such quantitative analysis suggests that GCE may be more impactful to younger patients with SAH.
Dietary choices in a generalist herbivore, the eastern cottontail Sylvilagus floridanus, in urban landscapes
Authors: Abu Baker Mohammad A. , Emerson Sara E. , Gorman Jessica , Brown Joel S. 
Published: February 2021

Abstract
We tested for dietary choices of foods varying in nutrient composition by cottontail rabbits on two college campuses in midwestern USA. We quantified choices among pellets of varying nutritional quality at artificial food patches. Dietary choices differed between seasons and locations. Spring giving-up densities (GUDs: food left behind) did not show differences in food choices and were lower than summer GUDs. In Appleton, the cottontails favoured both high protein and fibre pellets, whereas the medium protein and fibre pellets were favoured in Chicago. The cottontails maintained their choice of high protein, high fibre pellets at three spatial scales. The cottontails varied food intake to balance their protein, salt and fibre needs at different times and locations. Studying dietary choices and the effect of resource quality on foraging responses by urban wildlife provides a useful tool to study ecological interactions and can help minimize damage in urban environments such as parks.
Du Zaïre a la R.D. Du Congo : La Vieille Termitiere Terrassee par le Vent de la Savane
Authors: Ennes Erik 
Published: February 2021

From Zaire to the R.D. Congo: The Old Termite Hill Flattened by the Wind of the Savanna
This article concentrates mainly on the internal sources of the rapid breakdown of the Zairian state apparatus, deliberately not taking into account regional and international support for the warring parties. The Zairian state has been unable to manage its internal contradictions. This was driven to an extreme in the Kivu region, where the deeply seated crisis of representation was never adequately resolved. The absence of conflict-regulating institutions at the regional level was one enabling element for the rapid expansion of the Kivu conflict into •its regional and international ramifications. Another was the absence of any workable political alternative to armed struggle on the national level; neither the opposition, nor the government or the presidency was able to impose itself. In the general context of state decay, part of which was the implosion of the army, newcomers in the mining industry have initiated a take-over of key sectors of the Zairian economy, probably inducing a new mode of governance in the country.
Le Peuplement des Grassfields: Recherches Archeologiquesdans L’ouest du Cameroun
Authors: Lavachery Philippe 
Published: February 2021

The Settlement of the Grassfields: Archeological Research in the West of Cameroon
Until recently the Grassfields (Western Cameroon), cradle of the Bantu languages, were an unknown zone from an archaeological point of view. The excavations of Shum Laka rock shelter offer the first chrono-cultural sequence for the area. After 20 millenniums of microlithic (Late Stone Age) traditions of hunter-gatherers, a new culture with macrolithic tools, pottery and arboriculture (Stone to Metal Age) slowly developed from 6000 BC onwards. Correlation with palaeo-climatic and historical linguistic data suggests that proto-Benue-Congo and, later, proto-Bantu speakers could have been involved in these industries.
Het Locatiefsubstitutief in het Cilubà
Authors: Horvath Ellen , Kabuta Ngo Semzara 
Published: February 2021

The Locative Substitutive in Cilubà
In this article we will examine the correlation between tonology and syntax in connection with the locative substitutives (LS), or locative independent pronouns in Cilubà, spoken in both Kàsaayì provinces of Congo. We will show that the tonology of the LS depends on its syntactic position in the sentence. In contrast to the substitutives of classes 1 through 8 and 11 through 15 and of the participants, which generally have a fixed tone pattern, namely falling-high, the LS (classes 16 through 18) display three possible tone patterns, depending on their position in the sentence. These tone patterns are: falling-high, rising-low, high-low.