bluuebunny/crossref_metadata_2025 huggingface dataset:
SIGCSE Technical Symposium 2023 Report
Authors: Doyle Maureen , Stephenson Ben , Dorn Brian , Soh Leen-Kiat , Battestilli Lina , Stephens-Martinez Kristin , Yazdansepas Delaram
Published: July 2023

The 2023 SIGCSE Technical Symposium has come to a close. Thank you, all 1,554 of you, that joined us in Toronto and online for the first-ever SIGCSE Technical Symposium held outside the United States. We enjoyed welcoming 1,354 of you to Canada in person, as well as an additional 200 of you who registered for online attendance. While we didn't set a new attendance record, we did exceed last year's attendance, and look forward to seeing our attendance continue to grow back toward its pre-pandemic levels in 2024.
Using an Intelligent Robot to Introduce Elementary School Students to Computational Thinking and Artificial Intelligence
Authors: Touretzky David S.
Published: July 2023

In 2018 I received a SIGCSE Special Projects award to fund creation of computational thinking and artificial intelligence curriculum materials for students in grades 3-5 using my Calypso for Cozmo robot programming framework (https://Calypso.software) and the Cozmo robot from Anki. The work was done in collaboration with the New Brighton Area School District in New Brighton, Pennsylvania. The project succeeded, then failed, and may now be reborn again.
The Great Pirahã Brouhaha: Linguistic Diversity and Cognitive Universality
Authors: Chernela Janet
Published: July 2023

Claims made by linguist Daniel Everett, that the Pirahã language, spoken by a small group of native Amazonians, lacks features thought to be universally present in languages, captured the imaginations of scholars and prompted broader questions on the nature of language, the diversity in languages, and the universals shared by them. Everett claimed that, in Pirahã, he had found a language without numbers, colors, mythology, abstract thinking, or recursive embedding. These claims were challenged by proponents of a universal grammar and by other biological linguists concerned with identifying shared faculties that undergird human cognitive capacities and by linguistic anthropologists concerned with the products of those potentials as they are actualized in the interactivity of speaking. Situating the Pirahã in historical and sociological context, I question the novelty of a faculty of language and many of Everett's claims of Pirahã exceptionality, and I explore the renewed interest in the nature of language.
Recent Developments in the Archaeology of Long-Distance Connections Across the Ancient Indian Ocean
Authors: Abraham Shinu Anna
Published: July 2023

Scholarship on the ancient Indian Ocean, which stretches deep into the previous century, is available from an array of academic disciplines including but not limited to history, archaeology, epigraphy, numismatics, art history, and materials science. It spans from prehistory to the present era and includes evidence ranging from the Mediterranean to East Asia. What binds together the world of Indian Ocean research is an enduring interest in the complex maritime-based links crosscutting this space and—for archaeologists—the movements of cultural elements (objects, ideas, people, etc.) that have left behind some material trace. Recent field projects and materials science studies have greatly expanded this material database, refining (and sometimes challenging) traditional interpretations about Indian Ocean maritime relations. This review presents a streamlined perspective, focusing on recent archaeological contributions about long-distance interregional connections across the Indian Ocean from 500 bce to 1000 ce.
Filopodia In Vitro and In Vivo
Authors: Blake Thomas C.A. , Gallop Jennifer L.
Published: July 2023

Filopodia are dynamic cell surface protrusions used for cell motility, pathogen infection, and tissue development. The molecular mechanisms determining how and where filopodia grow and retract need to integrate mechanical forces and membrane curvature with extracellular signaling and the broader state of the cytoskeleton. The involved actin regulatory machinery nucleates, elongates, and bundles actin filaments separately from the underlying actin cortex. The refined membrane and actin geometry of filopodia, importance of tissue context, high spatiotemporal resolution required, and high degree of redundancy all limit current models. New technologies are improving opportunities for functional insight, with reconstitution of filopodia in vitro from purified components, endogenous genetic modification, inducible perturbation systems, and the study of filopodia in multicellular environments. In this review, we explore recent advances in conceptual models of how filopodia form, the molecules involved in this process, and our latest understanding of filopodia in vitro and in vivo.
Anodic Behaviour of Ni42Fe38Cu20 Electrode in Molten Fluoride Salts
Authors: Saevarsdottir Gudrun , Haarberg Geir Martin , Bourmaud Milane , Singh Kamaljeet , Padamata Sai Krishna
Published: July 2023

The anodic behaviour of Ni42Fe38Cu20 alloy at different sodium-potassium-cryolite-based electrolyte compositions was examined by chronopotentiometry, chronoamperometry, and linear sweep voltammetry at 1098 K for different electrolyte compositions. Steady-state anodic polarisation curves show that the anodic overpotential in electrolytes with molar ratio CR = (NaF+KF)/AlF3 = 1.4 is significantly less than in electrolyte with CR = 1.3. Short-term galvanostatic polarisation curves indicate that the potential difference between the anode and reference electrode (Al) was stable in electrolytes with CR = 1.4 and potassium ratio KR = KF/(KF + NaF) = 0.3 and CR = 1.4 KR = 0.35. The linear sweep voltammetry method indicates the presence of a diffusion-controlled reaction at a potential below the onset of oxygen evolution, which can be attributed to oxide formation. Tafel curves indicate the presence of the reactions below the potential of oxygen evolution but show a similar overpotential level for the oxygen-evolving reaction as for carbon anodes. Furthermore, the effect of pre-oxidation and influence of consistent polarisation on the anode performance was explored. Pre-oxidised anodes have better stability and lower exchange current density in similar experimental conditions compared to untreated anodes. It was also observed that leaving anodes unpolarised could lead to their instability and fluoridation of both types of anodes, with less severe effect on the pre-oxidised anode.
A Survey of the UK Pharmacy Profession’s Educational Needs on Pharmacogenomics
Authors: Rollinson Victoria , French Neil , Turner Richard , Pirmohamed Munir
Published: July 2023

Objective. The aim of this exploratory study was to ascertain the current educational status of pharmacogenomics (PGx) within the present and future UK pharmacy profession, in addition to ascertaining future educational and infrastructure needs of pharmacists to adopt PGx into practice. Methods. A 35-question survey was sent electronically to practicing pharmacists, preregistration pharmacists, and Master of Pharmacy (MPharm) students throughout the UK between April 2018 and May 2019. Responses were anonymous and analysed using GraphPad Prism 8 and SPSS statistics 26. Results. In total, 264 participants, where data could be used for analysis, responded to the survey. This comprised 196 practicing pharmacists and 68 preregistration pharmacists/MPharm students. The findings demonstrated variation in undergraduate level exposure to PGx between those who had qualified within the past 10 years and those who had qualified over 10 years ago. Over 60% of qualified pharmacists did not feel confident in identifying drugs that require PGx testing. Nearly three quarters of respondents cited that PGx guidelines were needed to help facilitate a PGx service, although 63.6% also stated that they had previously never looked for a PGx recommendation. Most respondents cited PGx as a low or medium learning priority. Conclusion. Our survey suggests that further education is required to prepare the UK pharmacy workforce for the advent of PGx. A focus on the provision of, and education around, PGx guidelines is needed. In addition, the disparity identified between pharmacists at different stages of their career will need to be addressed with tailored and targeted educational packages.
Effects of Dietary Thiamine Supplementation on Growth Performance, Digestive Enzymes’ Activity, and Biochemical Parameters of Beluga, Huso huso, Larvae
Authors: Mohseni Mahmoud , Ghelichpour Melika , Sayed Hassani Mir Hamed , Ollah Pajand Zabih , Ghorbani Vaghei Reza
Published: July 2023

Thiamine is a crucial nutrient in larval stage of fish, and thus, the present study aimed at evaluating the effects of dietary thiamine supplementation on survival, growth performance, and biochemical parameters of beluga, Huso huso, larvae. The fish larvae (50 ± 4.5 mg) were fed diets containing 0 (control), 5, 10, and 20 mg/kg thiamine for 26 days from 18 days after hatching to 44 days after hatching. Thiamine significantly increased the larvae survival, growth rate, digestive enzymes activity, and whole body protein and ash but decreased the whole body lipid and moisture

P
<
0.001

). Also, alanine amino transferase (ALT) and alkaline phosphatase (ALP) were decreased significantly in thiamine-treated groups (

P
<
0.05

). The highest survival and whole body ash were observed in 20 mg/kg thiamine treatment; the highest whole body protein and lipase activity were observed in 10 mg/kg thiamine treatment. The highest growth rate, amylase, and lowest whole body lipid, alanine amino transferase (ALT), and alkaline phosphatase (ALP) were observed in 10 and 20 mg/kg thiamine treatments. All thiamine-treated fish exhibited similar pepsin and chymotrypsin activities, all above the control fish. There were no significant effects of dietary thiamine supplementation on trypsin, whole body lysozyme, alternative complement (ACH50), lactate dehydrogenase (LDH) activities, and IgM levels. According to the results, 10–20 mg/kg dietary thiamine supplementation can increase the performance of beluga larvae by improving the health of liver and the activity of digestive system.
Challenges of Using IFNγ in Clinical Settings
Authors: Singh Snahlata , Chakrabarti Rumela
Published: July 2023

Cytokines in the tumor microenvironment can affect tumor growth, progression, and response to therapy, making them compelling therapeutic agents and targets. IFNγ is a pleiotropic cytokine predominantly secreted by immune cells that binds to its receptors IFNGR1 and IFNGR2 on target cells. Multiple clinical trials have investigated the efficacy of IFNγ in combination with other therapies for treating patients with cancer and have shown varying results. Here, we summarize the known effects of IFNγ signaling on tumor cells and explore the possibility of its use in clinical settings.
Understanding and Overcoming Immunosuppression Shaped by Cancer Stem Cells
Authors: Li Linheng , Jensen Roy A.
Published: July 2023

Use of immunotherapy in recent years has revolutionized cancer treatment for certain types of cancers. However, the broad utility of immunotherapy is limited because there are still many types of cancer that do not respond effectively. Failure of a cancer to respond is due, at least in part, to its phenotypic plasticity, a feature that is established by cancer stem cells (CSC) and their associated microenvironments. This article discusses the current understanding of CSC-mediated immune evasion and provides a prospective view on how researchers can better understand and overcome the intrinsic immune privilege of CSCs and the extrinsic immune-suppressive microenvironment shaped by them.
Structural Vulnerabilities in DLBCL for Enhanced Treatment Strategies
Authors: Cristaldi Vanessa , Lund Amanda W.
Published: July 2023

Diffuse large B-cell lymphoma (DLBCL) is a typically immune-suppressed lymphoma subtype with poor response to immune checkpoint blockade and chimeric antigen receptor T-cell therapy. Recent data demonstrated an association between an activated, myofibroblast-like tumor stroma with improved outcome. On the basis of these findings, Apollonio and colleagues explored the phenotypic, transcriptional, and functional state of fibroblastic reticular cells (FRC) in human and murine DLBCL. This study reveals that DLBCL cells trigger the activation and remodeling of FRCs, leading to a chronic inflammatory state that supports malignant B-cell survival. Transcriptional reprogramming of the FRCs may inhibit CD8+ T-cell migration and function through changes in homing chemokines, adhesion molecules, and antigen presentation machinery, which together limit the anti-DLBCL immune response. High-dimensional imaging mass cytometry revealed heterogeneous CD8+ T-cell and FRC neighborhoods that associated with different clinical outcomes and ex vivo modeling of the microenvironment indicated an opportunity to target the FRC network for improved T-cell motility, infiltration, and effector function. This research broadens our understanding of the complex interactions between the lymph node microarchitecture and antitumor immune surveillance, defines structural vulnerabilities in DLBCL, and thereby offers opportunities for combined therapeutic approaches.
Data from Site-Specific Cancer Incidence by Race and Immigration Status in Canada 2006–2015: A Population-Based Data Linkage Study
Authors: Malagón Talía , Morais Samantha , Tope Parker , El-Zein Mariam , Franco Eduardo L.
Published: July 2023

AbstractBackground:
The Canadian Cancer Registry (CCR) does not collect demographic data beyond age and sex, making it difficult to monitor health inequalities. Using data linkage, we compared site-specific cancer incidence rates by race.
Methods:
The 2006 and 2011 Canadian Census Health and Environment Cohorts are population-based probabilistically linked datasets of 5.9 million respondents of the 2006 long-form census and 6.5 million respondents of the 2011 National Household Survey. Race was self-reported. Respondent data were linked with the CCR up to 2015. We calculated age-standardized incidence rate ratios (ASIRR), comparing group-specific rates to the overall population rate with bootstrapped 95% confidence intervals (CI). We used negative binomial regressions to adjust for socioeconomic variables and assess interactions with immigration status.
Results:
The age-standardized overall cancer incidence rate was lower in almost all non-White racial groups than in the overall population, except for White and Indigenous peoples who had higher incidence rates than the overall population (ASIRRs, 1.03–1.04). Immigrants had substantially lower age-standardized overall cancer incidence rates than nonimmigrants (ASIRR, 0.83; 95% CI, 0.82–0.84). Stomach, liver, and thyroid cancers and multiple myelomas were the sites where non-White racial groups had consistently higher site-specific cancer incidence rates than the overall population. Immigration status was an important modifier of cancer risk in the interaction model.
Conclusions:
Differences in cancer incidence between racial groups are likely influenced by differences in lifestyles, early life exposures, and selection factors for immigration.
Impact:
Data linkage can help monitor health inequalities and assess progress in preventive interventions against cancer.

See related commentary by Withrow and Gomez, p. 876
Cancer Incidence by Race and Immigration Status in Canada: Value of Enhanced Sociodemographic Data for Disease Surveillance
Authors: Withrow Diana R. , Gomez Scarlett Lin
Published: July 2023

Metrics of cancer burden stratified by race can inform tailored prevention strategies. Examining how these metrics, such as incidence, vary by immigration status can provide insight into the drivers of differential cancer risk by race. The conduct of such analyses in Canada has historically been hindered by a lack of sociodemographic data in routine health data sources, including cancer registries. In their recent study, Malagón and colleagues overcome this challenge by using National Cancer Registry data linked to self-reported race and place of birth from the Canadian census. The study provides estimates of cancer incidence for 19 cancer sites across more than 10 racial groups. Compared with the total population, they found that cancer risk tended to be lower among persons belonging to non-White, non-Indigenous racial groups. Exceptions were stomach, liver, and thyroid cancers where incidence rates were higher in minority groups than in the White population. For some cancers and racial groups, incidence was lower irrespective of immigration status, suggesting the healthy immigrant effect may be sustained across generations or that other factors are also at play. The results highlight potential areas for deeper inquiry and underscore the value of sociodemographic data for disease surveillance.

See related article by Malagón et al., p. 906
Data from A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer
Authors: Leboulleux Sophie , Do Cao Christine , Zerdoud Slimane , Attard Marie , Bournaud Claire , Lacroix Ludovic , Benisvy Danielle , Taïeb David , Bardet Stéphane , Terroir-Cassou-Mounat Marie , Anizan Nadège , Bouvier-Morel Emilie , Lamartina Livia , Lion Georges , Betrian Sarah , Sajous Christophe , Schiazza Aurélie , Garcia Marie-Eve , Ciappuccini Renaud , Schlumberger Martin , Al Ghuzlan Abir , Godbert Yann , Borget Isabelle
Published: July 2023

AbstractPurpose:
To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.
Patients and Methods:
A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.
Results:
Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients.
Conclusions:
Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.
Data from Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04)
Authors: Mohan Arathi , Griffith Kent A. , Wuchu Fulei , Zhen David B. , Kumar-Sinha Chandan , Crysler Oxana , Hsiehchen David , Enzler Thomas , Dippman Dominique , Gunchick Valerie , Achreja Abhinav , Animasahun Olamide , Choppara Srinadh , Nenwani Minal , Chinnaiyan Arul M. , Nagrath Deepak , Zalupski Mark M. , Sahai Vaibhav
Published: July 2023

AbstractPurpose:
Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).
Patients and Methods:
Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Results:
In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable.
Conclusions:
Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.
Data from Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James , Hava David L. , Janku Filip
Published: July 2023

AbstractPurpose:
SYNB1891 is a live, modified strain of the probiotic Escherichia coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia, leading to STimulator of INterferon Genes (STING) activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways.
Patients and Methods:
This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral injections of SYNB1891 either alone or in combination with atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens.
Results:
Twenty-four participants received monotherapy across six cohorts, and 8 participants received combination therapy in two cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24 hours after the first intratumoral dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of IFN-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained predose and 7 days following the third weekly dose. In addition, a dose-related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies.
Conclusions:
Repeat intratumoral injection of SYNB1891 as monotherapy and in combination with atezolizumab was safe and well tolerated, and evidence of STING pathway target engagement was observed.
Data from Preclinical Characterization and Phase 1 Trial Results of INBRX-109, a Third-Generation, Recombinant, Humanized, Death Receptor 5 Agonist Antibody, in Chondrosarcoma
Authors: Subbiah Vivek , Chawla Sant P. , Conley Anthony P. , Wilky Breelyn A. , Tolcher Anthony , Lakhani Nehal J. , Berz David , Andrianov Vasily , Crago William , Holcomb Monica , Hussain Abrahim , Veldstra Carson , Kalabus James , O’Neill Brianne , Senne Lane , Rowell Emily , Heidt Analeah B. , Willis Katelyn M. , Eckelman Brendan P.
Published: July 2023

Abstract
Purpose: Patients with unresectable/metastatic chondrosarcoma have poor prognoses; conventional chondrosarcoma is associated with a median progression-free survival (PFS) of <4 months after first-line chemotherapy. No standard targeted therapies are available. We present the preclinical characterization of INBRX-109, a third-generation death receptor 5 (DR5) agonist, and clinical findings from a phase 1 trial of INBRX-109 in unresectable/metastatic chondrosarcoma (NCT03715933). Patients and Methods: INBRX-109 was first characterized preclinically as a DR5 agonist, with binding specificity and hepatotoxicity evaluated in vitro and antitumor activity evaluated both in vitro and in vivo. INBRX-109 (3 mg/kg every 3 weeks) was then evaluated in a phase 1 study of solid tumors that included a cohort with any subtype of chondrosarcoma and a cohort with IDH1/IDH2-mutant conventional chondrosarcoma. The primary endpoint was safety. Efficacy was an exploratory endpoint, with measures including objective response, disease control rate, and PFS. Results: In preclinical studies, INBRX-109 led to antitumor activity in vitro and in patient-derived xenograft models, with minimal hepatotoxicity. In the phase 1 study, INBRX-109 was well tolerated and demonstrated antitumor activity in unresectable/metastatic chondrosarcoma. INBRX-109 led to a disease control rate of 87.1% (27/31; durable clinical benefit, 40.7% [11/27]), including 2 partial responses, and median PFS of 7.6 months. Most treatment-related adverse events, including liver-related events, were low grade (grade ≥3 events in chondrosarcoma cohorts, 5.7%). Conclusions: INBRX-109 demonstrated encouraging antitumor activity with a favorable safety profile in patients with unresectable/metastatic chondrosarcoma. A randomized, placebo-controlled, phase 2 trial (ChonDRAgon, NCT04950075) will further evaluate INBRX-109 in conventional chondrosarcoma.
Data from Early changes in circulating cell free KRAS G12C predicts response to adagrasib in KRAS mutant non-small cell lung cancer patients
Authors: Paweletz Cloud P. , Heavey Grace A. , Kuang Yanan , Durlacher Emily , Kheoh Thian , Chao Richard C. , Spira Alexander I. , Leventakos Konstantinos , Johnson Melissa L. , Ou Sai-Hong Ignatius. , Riely Gregory J. , Anderes Kenna , Yang Wenjing , Christensen James G. , Janne Pasi A.
Published: July 2023

Abstract
Purpose: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRASG12C-mutant lung cancer patients that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared to clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial ~3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA >90% and 33 pts (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared to patients with incomplete ctDNA clearance (60.6% vs 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 months vs 5.4 months) and progression free survival (HR 0.3). Conclusion: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
PreCancer Atlas: Present and Future
Authors: Srivastava Sudhir , Wagner Paul D. , Hughes Shannon K. , Ghosh Sharmistha
Published: July 2023

Precancer atlases have the potential to revolutionize how we think about the topographic and morphologic structures of precancerous lesions in relation to cellular, molecular, genetic, and pathophysiologic states. This mini review uses the Human Tumor Atlas Network (HTAN), established by the National Cancer Institute (NCI), to illustrate the construction of cellular and molecular three-dimensional atlases of human cancers as they evolve from precancerous lesions to advanced disease. We describe the collaborative nature of the network and the research to determine how and when premalignant lesions progress to invasive cancer, regress or obtain a state of equilibrium. We have attempted to highlight progress made by HTAN in building precancer atlases and discuss possible future directions. It is hoped that the lessons from our experience with HTAN will help other investigators engaged in the construction of precancer atlases to crystallize their thoughts on logistics, rationale, and implementation.
Comparison Study of FNAC Using the Milan System Cytopathology versus Definitive Histology for the Diagnosis of Salivary Gland Tumors
Authors: Palacios-Garcia José María , Vizcarra-Melgar Julissa , Merchante-Ruiz Maria , Perez Manuel , Álvarez-Cendrero Marta , Sánchez-Gómez Serafín
Published: July 2023

Introduction: Salivary gland tumors (SGT) represent 6 to 8 percent of head and neck tumors. The cytologic diagnosis of SGT is performed by fine-needle aspiration cytology (FNAC) with variable sensitivity and specificity. The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) categorizes the cytological results and provides the risk of malignancy (ROM). The aim of our study was to evaluate the cytological findings with the definitive pathological findings to assess the sensitivity, specificity, and diagnostic accuracy of FNAC in SGT according to MSRSGC classification. Method: An observational, retrospective, single-center study was carried out at a tertiary referral hospital over a period of 10 years. Patients that underwent FNAC for major SGT and that have undergone surgery to remove the tumor were included. A histopathological follow-up was performed on the surgically excised lesions. Results from the FNAC were categorized into one of the six MSRSGC categories. The sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of FNAC for determining benign and malignant cases were calculated. Results: A total of 417 cases were analyzed. The cytological prediction of ROM was 10% in nondiagnostic, 12.12% in non-neoplastic, 3.58% in neoplasm benign group, 60% in AUS and SUMP groups, and 100% in suspicious and malignant group. The statistical analysis of sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for determining benign cases was 99%, 55%, 94%, 93%, and 94%, respectively, and for determining malignant neoplasm was 54%, 99%, 93%, 94%, and 94%, respectively. Conclusion: In our hands, MSRSGC is highly sensitive for benign tumors and highly specific for malignant tumors. The low sensitivity to differentiate malignant from benign cases makes it necessary to apply an adequate anamnesis, physical examination, and imaging tests to consider surgical treatment in most cases.
The Association of Dexamethasone and Hydrocortisone with Cerebellar Growth in Premature Infants
Authors: Warmerdam Laura A. , van Wezel-Meijler Gerda , de Vries Linda S , Groenendaal Floris , Steggerda Sylke J.
Published: July 2023

Objectives: Corticosteroids are used to prevent or treat lung disease of prematurity. While neurological side effects have been reported, detailed effects on cerebellar growth are unknown. This study aimed to compare cerebellar growth in premature infants who received dexamethasone or hydrocortisone to premature infants who did not receive postnatal corticosteroids. Study Design: Retrospective case-control study in infants born at a gestational age of <29 weeks and admitted to two level 3 neonatal intensive care units. Exclusion criteria were severe congenital anomalies and cerebellar or severe supratentorial lesions. Infants were treated with dexamethasone (unit 1) or hydrocortisone (unit 2) for chronic lung disease. Controls (unit 1) did not receive postnatal corticosteroids. Sequential head circumference (HC) and ultrasound measurements of transcerebellar diameter (TCD), biparietal diameter (BPD), and corpus callosum-fastigium length (CCFL) were performed until 40 weeks’ postmenstrual age (PMA). Growth was assessed using linear mixed models correcting for PMA at measurement, sex, HC z-score at birth, and a propensity score indicating illness severity. Group differences before treatment were assessed using linear regression. Results: 346 infants were included (68 dexamethasone, 37 hydrocortisone, 241 controls). Before starting corticosteroids, TCD, BPD, and HC measurements did not differ between patients and controls at a comparable PMA. After starting treatment, both types of corticosteroid had a negative association with TCD growth. BPD, CCFL, and HC growth were not negatively affected. Conclusion: Administration of dexamethasone and hydrocortisone are both associated with impaired cerebellar growth in premature infants without evident negative associations with cerebral growth.
Parkinson’s Disease: A Tale of Many Players
Authors: Pauwels Ernest K.J. , Boer Gerard J.
Published: July 2023

In 2020, more than 9 million patients suffering from Parkinson’s disease (PD) were reported worldwide, and studies predict that the burden of this disease will grow substantially in industrial countries. In the last decade, there has been a better understanding of this neurodegenerative disorder, clinically characterized by motor disturbances, impaired balance, coordination, memory difficulties, and behavioral changes. Various preclinical investigations and studies on human postmortem brains suggest that local oxidative stress and inflammation promote misfolding and aggregation of alpha-synuclein within Lewy bodies and cause nerve cell damage. Parallel to these investigations, the familial contribution to the disease became evident from studies on genome-wide association in which specific genetic defects were linked to neuritic alpha-synuclein pathology. As for treatment, currently available pharmacological and surgical interventions may improve the quality of life but do not stop the progress of neurodegeneration. However, numerous preclinical studies have provided insights into the pathogenesis of PD. Their results provide a solid base for clinical trials and further developments. In this review, we discuss the pathogenesis, the prospects, and challenges of synolytic therapy, CRISPR, gene editing, and gene- and cell-based therapy. We also throw light on the recent observation that targeted physiotherapy may help improve the gait and other motor impairments.
Implications of Social Disadvantage Score in Cardiovascular Outcomes and Risk Assessment: Findings From the Multi-Ethnic Study of Atherosclerosis
Authors: Hammoud Aziz , Chen Haiying , Ivanov Alexander , Yeboah Joseph , Nasir Khurram , Cainzos-Achirica Miguel , Bertoni Alain , Khan Safi U. , Blaha Michael , Herrington David , Shapiro Michael D.
Published: July 2023

BACKGROUND:

Social determinants of health contribute to disparate cardiovascular outcomes, yet they have not been operationalized into the current paradigm of cardiovascular risk assessment.

METHODS:

Data from the Multi-Ethnic Study of Atherosclerosis, which includes participants from 6 US field centers, were used to create an index of baseline Social Disadvantage Score (SDS) to explore its association with incident atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality and impact on ASCVD risk prediction. SDS, which ranges from 0 to 4, was calculated by tallying the following social factors: (1) household income less than the federal poverty level; (2) educational attainment less than a high school diploma; (3) single-living status; and (4) experience of lifetime discrimination. Cox models were used to examine the association between SDS and each outcome with adjustment for traditional cardiovascular risk factors. Changes in the discrimination and reclassification of ASCVD risk by incorporating SDS into the pooled cohort equations were examined.

RESULTS:

A total of 6434 participants (mean age, 61.9±10.2 years; female 52.8%; non-white 60.9%) had available SDS 1733 (26.9%) with SDS 0; 2614 (40.6%) with SDS 1; 1515 (23.5%) with SDS 2; and 572 (8.9%) with SDS ≥3. In total, 775 incident ASCVD events and 1573 deaths were observed over a median follow-up of 17.0 years. Increasing SDS was significantly associated with incident ASCVD and all-cause mortality after adjusting for traditional risk factors (ASCVD: per unit increase in SDS hazard ratio, 1.15 [95% CI, 1.07–1.24]; mortality: per unit increase in SDS hazard ratio, 1.13 [95% CI, 1.08–1.19]). Adding SDS to pooled cohort equations components in a Cox model for 10-year ASCVD risk prediction did not significantly improve discrimination (
P
=0.208) or reclassification (
P
=0.112).

CONCLUSIONS:

Although SDS is independently associated with incident ASCVD and all-cause mortality, it does not improve 10-year ASCVD risk prediction beyond pooled cohort equations.
Epileptogenic networks in extra temporal lobe epilepsy
Authors: Hall Gerard R. , Hutchings Frances , Horsley Jonathan , Simpson Callum M. , Wang Yujiang , de Tisi Jane , Miserocchi Anna , McEvoy Andrew W. , Vos Sjoerd B. , Winston Gavin P. , Duncan John S. , Taylor Peter N.
Published: July 2023

Extra temporal lobe epilepsy (eTLE) may involve heterogenous widespread cerebral networks. We investigated the structural network of an eTLE cohort, at the postulated epileptogenic zone later surgically removed, as a network node: the resection zone (RZ). We hypothesized patients with an abnormal connection to/from the RZ to have proportionally increased abnormalities based on topological proximity to the RZ, in addition to poorer post-operative seizure outcome. Structural and diffusion MRI were collected for 22 eTLE patients pre- and post-surgery, and for 29 healthy controls. The structural connectivity of the RZ prior to surgery, measured via generalized fractional anisotropy (gFA), was compared with healthy controls. Abnormal connections were identified as those with substantially reduced gFA (z < −1.96). For patients with one or more abnormal connections to/from the RZ, connections with closer topological distance to the RZ had higher proportion of abnormalities. The minority of the seizure-free patients (3/11) had one or more abnormal connections, while most non-seizure-free patients (8/11) had abnormal connections to the RZ. Our data suggest that eTLE patients with one or more abnormal structural connections to/from the RZ had more proportional abnormal connections based on topological distance to the RZ and associated with reduced chance of seizure freedom post-surgery.
FRMT: A Benchmark for Few-Shot Region-Aware Machine Translation
Authors: Riley Parker , Dozat Timothy , Botha Jan A. , Garcia Xavier , Garrette Dan , Riesa Jason , Firat Orhan , Constant Noah
Published: July 2023

We present FRMT, a new dataset and evaluation benchmark for Few-shot Region-aware Machine Translation, a type of style-targeted translation. The dataset consists of professional translations from English into two regional variants each of Portuguese and Mandarin Chinese. Source documents are selected to enable detailed analysis of phenomena of interest, including lexically distinct terms and distractor terms. We explore automatic evaluation metrics for FRMT and validate their correlation with expert human evaluation across both region-matched and mismatched rating scenarios. Finally, we present a number of baseline models for this task, and offer guidelines for how researchers can train, evaluate, and compare their own models. Our dataset and evaluation code are publicly available: https://bit.ly/frmt-task.
OpenFact: Factuality Enhanced Open Knowledge Extraction
Authors: Song Linfeng , Wang Ante , Pan Xiaoman , Zhang Hongming , Yu Dian , Jin Lifeng , Mi Haitao , Su Jinsong , Zhang Yue , Yu Dong
Published: July 2023

We focus on the factuality property during the extraction of an OpenIE corpus named OpenFact, which contains more than 12 million high-quality knowledge triplets. We break down the factuality property into two important aspects—expressiveness and groundedness—and we propose a comprehensive framework to handle both aspects. To enhance expressiveness, we formulate each knowledge piece in OpenFact based on a semantic frame. We also design templates, extra constraints, and adopt human efforts so that most OpenFact triplets contain enough details. For groundedness, we require the main arguments of each triplet to contain linked Wikidata1 entities. A human evaluation suggests that the OpenFact triplets are much more accurate and contain denser information compared to OPIEC-Linked (Gashteovski et al., 2019), one recent high-quality OpenIE corpus grounded to Wikidata. Further experiments on knowledge base completion and knowledge base question answering show the effectiveness of OpenFact over OPIEC-Linked as supplementary knowledge to Wikidata as the major KG.
On Graph-based Reentrancy-free Semantic Parsing
Authors: Petit Alban , Corro Caio
Published: July 2023

We propose a novel graph-based approach for semantic parsing that resolves two problems observed in the literature: (1) seq2seq models fail on compositional generalization tasks; (2) previous work using phrase structure parsers cannot cover all the semantic parses observed in treebanks. We prove that both MAP inference and latent tag anchoring (required for weakly-supervised learning) are NP-hard problems. We propose two optimization algorithms based on constraint smoothing and conditional gradient to approximately solve these inference problems. Experimentally, our approach delivers state-of-the-art results on GeoQuery, Scan, and Clevr, both for i.i.d. splits and for splits that test for compositional generalization.
Lagenandra limbusleviterapertae, a new addition to the genus Lagenandra (Araceae) from Sri Lanka
Authors: MADOLA INDRAKHEELA , YAKANDAWALA DEEPTHI , YAKANDAWALA KAPILA
Published: July 2023

Lagenandra limbusleviterapertae, a new species of Lagenandra from the Hiyare Forest Reserve, Galle District is described and illustrated. The new species can be differentiated from all other described Lagenandra species on the basis of the linear limb, where the limb opens only at the base of the tail extending only about 1/5 of the length and the width of the opening remains < 5 mm. Detailed morphological characters, diagnostic comparisons, notes on habitat and ecology are presented. Based on the IUCN Red List categories and criteria, the new species is assessed as Critically Endangered under Criterion B1ab(iii, v)+B2ab(iii, v)+C2a(i).
Shared control based on ANFIS for brain-controlled driving
Authors: Dong Na , Wu Zhiqiang , Gao Zhongke
Published: July 2023

Using electroencephalography (EEG) signals to drive a vehicle could help disabled people expand their range of motion and improve their independence. A brain-controlled vehicle (BCV) is a vehicle that is commanded by analyzing EEG signals. However, the analysis and transmission effect of EEG signals is not ideal, the driving performance of the BCV solely relying on EEG signals is relatively poor. In this paper, to solve this problem, we propose a dynamic shared control method based on adaptive network-based fuzzy inference system (ANFIS). First, an ANFIS intelligent controller is designed to automatically make decisions according to the state of the vehicle. Then, safety coefficient and intention coefficient are proposed to evaluate the safety and driving intention of the brain-controlled driver. Finally, a fuzzy controller with safety and intention coefficients as inputs and brain-controlled driver weights as outputs is designed. The controller is the embodiment of a human–machine interaction, which allows the driver to maintain maximum control authority over the BCV under safe conditions by dynamically balancing the control authority of the brain-controlled driver and the ANFIS controller on the BCV. To verify the effectiveness of the proposed method, a joint simulation platform of Carsim and Matlab is established, and several groups of comparative simulation experiments are carried out, through which, it is demonstrated that the proposed method can effectively avoid road deviation while well maintaining the control authority of the brain-controlled driver.
The Effects of Language-Related Misunderstanding at Work
Authors: Fiset John , Bhave Devasheesh P. , Jha Nilotpal
Published: July 2023

Demographic, technological, and global trends have brought the language used at the workplace to the forefront. A growing body of research reveals that language could result in misunderstanding at work, and influence employees’ performance and attitudinal outcomes. Language at work encompasses standard language (e.g., English) as well as several hybrid forms of language (non-native accents, code-switching, and jargon). We delineate how these forms of language could result in misunderstanding. We then identify relational, affective, and informational mechanisms that underlie the relationship between language-related misunderstanding and employees’ performance and attitudinal outcomes, and highlight key boundary conditions. In doing so, we uncover research gaps and identify areas for future research. We conclude with implications for theory as well as for practitioners to navigate language-related misunderstanding at work.
Talking to the enemy: Explaining the emergence of peace talks in interstate war
Authors: Mastro Oriana Skylar , Siegel David A
Published: July 2023

Why are some states open to talking while fighting while others are not? We argue that a state considering opening negotiations is concerned not only with the adverse inference that the opposing state will draw, but also the actions that the opposing state might take in response to that inference. We use a formal model, with assumptions grounded in extensive historical evidence, to highlight one particular response to opening negotiations—the escalation of war efforts—and one particular characteristic of the state opening negotiations—its resilience to escalation. We find that states are willing to open negotiations under two conditions: when their opponents find escalation too costly, and when there is a signal of high resilience that only the highly resilient care to use. To illustrate the dynamics of the second condition, we offer an extended case study detailing North Vietnam’s changing approach to negotiations during the Vietnam War.
The feline skin microbiome: interrelationship between health and disease
Authors: Older Caitlin E , Hoffmann Aline Rodrigues , Diesel Alison B
Published: July 2023

Practical relevance:

As with other species, the skin microbiome of cats has been assessed over the past few years utilizing modern technologies. This has resulted in the identification of many more bacterial and fungal organisms compared with what had been recorded historically on the skin in various states of health and disease using culture-based studies. This information is expanding the knowledge of how microbial communities are impacted by various changes in the skin health of cats. More specifically, how these microbial communities change in the face of health and disease, and how various therapeutic interventions affect the cutaneous microbiome, lends a greater understanding of disease pathogenesis and provides a growing area of research for correcting dysbiosis and improving feline skin health.

Evidence base:

Most studies on the feline skin microbiome thus far have been descriptive in nature. These provide a framework for the next level of investigations on how various states of health and disease impact the products produced by the cutaneous microbiome (ie, the cutaneous metabolome), as well as how targeted interventions may promote the restoration of balance.

Aims:

This review aims to summarize what is currently known about the feline cutaneous microbiome and its clinical implications. The role of the skin microbiome in health and disease, the current state of research in this area and the potential for future studies to produce targeted interventions for cats are a particular focus.