bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas
Authors: Wo Jennifer Y. , Clark Jeffrey W. , Eyler Christine E. , Mino-Kenudson Mari , Klempner Samuel J. , Allen Jill N. , Keane Florence K. , Parikh Aparna R. , Roeland Eric , Drapek Lorraine C. , Ryan David P. , Corcoran Ryan B. , Van Seventer Emily , Fetter Isobel J. , Shahzade Heather A. , Khandekar Melin J. , Lanuti Michael , Morse Christopher R. , Heist Rebecca S. , Ulysse Christine A. , Christopher Benjamin , Baglini Christian , Yeap Beow Y. , Mullen John T. , Hong Theodore S. 
Published: July 2021

AbstractPurpose:We performed a NCI-sponsored, prospective study of neoadjuvant FOLFIRINOX followed by chemoradiation with carboplatin/paclitaxel followed by surgery in patients with locally advanced gastric or gastroesophageal cancer.Patients and Methods:The primary objective was to determine completion rate of neoadjuvant FOLFIRINOX × 8 followed by chemoradiation. Secondary endpoints were toxicity and pathologic complete response (pCR) rate. Exploratory analysis was performed of circulating tumor DNA (ctDNA) to treatment response.Results:From October 2017 to June 2018, 25 patients were enrolled. All patients started FOLFIRINOX, 92% completed all eight planned cycles, and 88% completed chemoradiation. Twenty (80%) patients underwent surgical resection, and 7 had a pCR (35% in resected cohort, 28% intention to treat). Tumor-specific mutations were identified in 21 (84%) patients, of whom 4 and 17 patients had undetectable and detectable ctDNA at baseline, respectively. Presence of detectable post-chemoradiation ctDNA (P = 0.004) and/or postoperative ctDNA (P = 0.045) were associated with disease recurrence.Conclusions:Here we show neoadjuvant FOLFIRINOX followed by chemoradiation for locally advanced gastroesophageal cancer is feasible and yields a high rate of pCR. ctDNA appears to be a promising predictor of postoperative recurrence.See related commentary by Catenacci, p. 6281
SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation
Authors: Adolphe Christelle , Millar Amanda , Kojic Marija , Barkauskas Deborah S. , Sundström Anders , Swartling Fredrik J. , Hediyeh-zadeh Soroor , Tan Chin Wee , Davis Melissa J. , Genovesi Laura A. , Wainwright Brandon J. 
Published: July 2021

AbstractMedulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors (GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9low GCP-like tumor cells constitute the bulk of both infant (Math1Cre:Ptch1lox/lox) and adult (Ptch1LacZ/+) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9+MATH1+ (GCP), SOX9+GFAP+ (astrocytes) and SOX9+MATH1+GFAP+ (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9lox/lox) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1lox/lox;Sox9lox/lox) does not affect tumor formation.Implications:Despite preclinical data indicating SOX9 plays a key role in SHH-MB biology, our data argue against SOX9 as a viable therapeutic target.
The PI3K/mTOR Inhibitor Ompalisib Suppresses Nonhomologous End Joining and Sensitizes Cancer Cells to Radio- and Chemotherapy
Authors: Du Jie , Chen Fuqiang , Yu Jiahua , Jiang Lijun , Zhou Meijuan 
Published: July 2021

Abstract
As the predominant pathway for the repair of DNA double-strand breaks (DSB), non-homologous end joining (NHEJ) attenuates the efficacy of cancer treatment which relies on the introduction of DSBs, such as radiotherapy and genotoxic drugs. Identifying novel NHEJ inhibitors is of great importance for improving the therapeutic efficiency of radio- or chemotherapy. Here we miniaturized our recently developed NHEJ detecting system into a 96-well plate-based format and interrogated an FDA approved drug library containing 1732 compounds. A collection of novel hits were considered to be potential DSB repair inhibitors at the noncytotoxic concentration. We identified omipalisib as an efficient sensitizer for DNA damage–induced cell death in vitro. Furthermore, in vitro analysis uncovered the repressive effect of omipalisib on the phosphorylation of DNA-dependent protein kinase catalytic subunit induced by ionizing radiation and doxorubicin, which led to the suppression of NHEJ pathway.

Implications:
In summary, our findings suggested the possibility for repurposing these candidates as radio- or chemosensitizers, which might extend their clinical application in cancer therapy.
Longitudinal Analysis of Human Pancreatic Adenocarcinoma Development Reveals Transient Gene Expression Signatures
Authors: Kim Jungsun , Ekstrom Taelor , Yang Wenli , Donahue Greg , Grygoryev Dmytro , Ngo Thuy T.M. , Muschler John L. , Morgan Terry , Zaret Kenneth S. 
Published: July 2021

Abstract

Previous transcriptome studies of human pancreatic ductal adenocarcinoma (PDAC) compare non-cancerous pancreatic intraepithelial neoplasias (PanIN) with late-stage PDAC obtained from different patients, thus have limited ability to discern network dynamics that contribute to the disease progression. We demonstrated previously that the 10-22 cell line, an induced pluripotent stem cell–like line reprogrammed from late-stage human PDAC cells, recapitulated the progression from PanINs to PDAC upon transplantation into NOD/LtSz-scid/IL2R-gammanull mice. Herein, we investigated the transition from precursor to PDAC using the isogenic model. We analyzed transcriptomes of genetically tagged 10-22 cells progressing from PanINs to PDAC in mice and validated the results using The Cancer Genome Atlas PDAC dataset, human clinical PanIN and PDAC tissues, and a well-established murine PDAC model. We functionally studied candidate proteins using human normal (H6C7) and cancerous (Miapaca2, Aspc1) pancreatic ductal epithelial cell lines. 10-22 cell–derived PDAC displayed the molecular signature of clinical human PDAC. Expression changes of many genes were transient during PDAC progression. Pathways for extracellular vesicle transport and neuronal cell differentiation were derepressed in the progression of PanINs to PDAC. HMG-box transcription factor 1 (HBP1) and BTB domain and CNC homolog 1 (BACH1) were implicated in regulating dynamically expressed genes during PDAC progression, and their expressions inversely correlated with PDAC patients' prognosis. Ectopic expression of HBP1 increased proliferation and migration of normal and cancerous pancreatic cells, indicating that HBP1 may confer the cell dissemination capacity in early PDAC progression. This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis.

Implications:
Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.
Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression
Authors: Lai Shu-Chin Alicia , Gundlapalli Harika , Ekiz H. Atakan , Jiang Amanda , Fernandez Elvelyn , Welm Alana L. 
Published: July 2021

AbstractImmunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide a strong preclinical rationale to pursue small-molecule Ron kinase inhibitors for the prevention and treatment of metastatic breast cancer.Significance:The discovery that SF-Ron promotes antitumor immune responses has significant clinical implications. Therapeutic antibodies targeting full-length Ron may not be effective for immunotherapy; poor efficacy of such antibodies in trials may be due to their inability to block SF-Ron. Our data warrant trials with inhibitors targeting SF-Ron in combination with immunotherapy.This article is highlighted in the In This Issue feature, p. 2945
Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot
Authors: Reuter Miriam S. , Chaturvedi Rajiv R. , Jobling Rebekah K. , Pellecchia Giovanna , Hamdan Omar , Sung Wilson W.L. , Nalpathamkalam Thomas , Attaluri Pratyusha , Silversides Candice K. , Wald Rachel M. , Marshall Christian R. , Williams Simon G. , Keavney Bernard D. , Thiruvahindrapuram Bhooma , Scherer Stephen W. , Bassett Anne S. 
Published: July 2021

Background:
Tetralogy of Fallot (TOF)—the most common cyanotic heart defect in newborns—has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes and could contribute to delineating pathomechanisms.

Methods:
Using a clinically driven strategy, we reanalyzed exome sequencing data from 811 probands with TOF, to identify rare loss-of-function and other likely pathogenic variants in genes associated with congenital heart disease.

Results:

We confirmed a major contribution of likely pathogenic variants in
FLT4
(VEGFR3 [vascular endothelial growth factor receptor 3]; n=14) and
NOTCH1
(n=10) and identified 1 to 3 variants in each of 21 other genes, including
ATRX
,
DLL4
,
EP300
,
GATA6
,
JAG1
,
NF1
,
PIK3CA
,
RAF1
,
RASA1
,
SMAD2
, and
TBX1
. In addition, multiple loss-of-function variants provided support for 3 emerging congenital heart disease/TOF candidate genes:
KDR
(n=4),
IQGAP1
(n=3), and
GDF1
(n=8). In total, these variants were identified in 63 probands (7.8%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (
P
=3.3×10
−16
), with VEGFR2 (vascular endothelial growth factor receptor 2;
KDR
) and NOTCH1 (neurogenic locus notch homolog protein 1) representing central nodes. Variants associated with arrhythmias/sudden death and heart failure indicated factors that could influence long-term outcomes.

Conclusions:

The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, with further evidence for
KDR
(VEGFR2) as a congenital heart disease/TOF gene and for VEGF (vascular endothelial growth factor) and Notch signaling as mechanisms in human disease. Harnessing the genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.
Updating the Authentication of Digital Evidence in the International Criminal Court
Authors: Braga da Silva Rafael 
Published: July 2021

Abstract
This paper discusses the issue of authenticity of digital evidence in the icc. While some types of digital evidence have been used at the icc, some challenges persist. icc Chambers have used old methods of verifying the authenticity of physical documents to analyze pieces of digital evidence. These practices do not fully grasp the issue of authenticity in relation to a piece of digital evidence, which may require specific practices and technologies. This paper discusses how icc judges can update its practices in order to address such issue. With an ever-growing use of digital evidence in its courtroom, it is essential for icc Judges to develop solid practices that allow them to fully examine the authenticity of a piece of digital evidence. This paper claims that such adaptations may require capacity-building for judges, as well as changes in the evidence management system and in the icc legal framework.
An Historical Assessment and Analysis of Economic Imperialism in West Africa
Authors: Omobowale Ayokunle Olumuyiwa , Sawadogo Natewinde 
Published: July 2021

Abstract
The West African political economy has been shaped by the policies, decisions and actions of dominant European imperialist countries since about over 500 years. Starting with imperial merchant capitalism along the West African coast in the 16th Century and French gradual acquisition of Senegal as a colony as from 1677, West Africa has remained under the imperialist hold. West Africa remains economically dependent on its former colonial masters despite more than 60 years since the countries started gaining independence. The consequences of economic imperialism on West Africa have included exploitative resource extraction, proxy and resource influenced civil wars, illegal trade in natural resources, mass poverty, and external migration of skilled workers necessary for national development. The world sees and broadcasts poverty, starvation, conflict and Saharan migration in the West African sub-continent, but hardly reports the exploitative imperialistic processes that have produced poverty and misery in West Africa in particular and across sub-Saharan Africa in general.
Sources of Subseasonal Skill and Predictability in Wintertime California Precipitation Forecasts
Authors: L’Heureux Michelle L. , Tippett Michael K. , Becker Emily J. 
Published: July 2021

AbstractThe relation between the El Niño–Southern Oscillation (ENSO) and California precipitation has been studied extensively and plays a prominent role in seasonal forecasting. However, a wide range of precipitation outcomes on seasonal time scales are possible, even during extreme ENSO states. Here, we investigate prediction skill and its origins on subseasonal time scales. Model predictions of California precipitation are examined using Subseasonal Experiment (SubX) reforecasts for the period 1999–2016, focusing on those from the Flow-Following Icosahedral Model (FIM). Two potential sources of subseasonal predictability are examined: the tropical Pacific Ocean and upper-level zonal winds near California. In both observations and forecasts, the Niño-3.4 index exhibits a weak and insignificant relationship with daily to monthly averages of California precipitation. Likewise, model tropical sea surface temperature and outgoing longwave radiation show only minimal relations with California precipitation forecasts, providing no evidence that flavors of El Niño or tropical modes substantially contribute to the success or failure of subseasonal forecasts. On the other hand, an index for upper-level zonal winds is strongly correlated with precipitation in observations and forecasts, across averaging windows and lead times. The wind index is related to ENSO, but the correlation between the wind index and precipitation remains even after accounting for ENSO phase. Intriguingly, the Niño-3.4 index and California precipitation show a slight but robust negative statistical relation after accounting for the wind index.
Education and skills training for care partners of hospitalised older adults: A scoping review
Authors: Carbery Madeline , Schwartz Samantha , Werner Nicole , Fields Beth 
Published: July 2021

Background: The care partners of hospitalised older adults often feel dissatisfied with the education and skills training provided to them, resulting in unpreparedness and poor health outcomes. Objective: This review aimed to characterise and identify gaps in the education and skills training used with the care partners of older adults in the hospital. Methods: We conducted a scoping review on the education and skills training practices used with the care partners of hospitalised older adults in the USA via sources identified in the PubMed, PsychINFO and CINAHL databases. Results: Twelve studies were included in this review. Results illustrate that nurses utilise multiple modes of delivery and frequently provide education and skills training tailored to the needs of care partners at the latter end of hospital care. The provision of education and skills training varies greatly, however, including who provides education, in what way information is conveyed, and how care partner outcomes are measured. Conclusion: This is the first scoping review to describe and synthesise the education and skills training practices used with care partners of hospitalised older adults. Findings highlight the need for education and skills training to be interprofessional, tailored to individual care partners’ needs and begin at, or even before, the hospital admission of older adult patients.
Love, sex, drugs and women’s sub-optimal adherence to MDR-TB treatment in South Africa: Opportunities for enhanced health education
Authors: Mugoni Petronella Chipo 
Published: July 2021

Objective: Rising incidence of acquired multidrug-resistant tuberculosis (MDR-TB) in South Africa suggests low knowledge and implementation of infection prevention and control strategies in household and congregate settings. This study contributes to the under-researched area of non-biomedical responses to sub-adherence to treatment. Design: The study utilises a quasi-ethnographic qualitative case study of 10 women aged 18 to 34 years to understand their treatment adherence behaviours through the lens of their sex, gender, age, cultural beliefs and socio-economic status. Setting: This study investigated reasons for young women’s sub-optimal adherence to treatment for acquired MDR-TB in eThekwini Metro, KwaZulu-Natal province, South Africa, which records high burdens of tuberculosis (TB), MDR-TB and HIV. Methods: Primary data were collected from 20 participants who were selected through criterion, purposive and snowball sampling. Data were gathered through focus group discussions with women being treated for transmitted MDR-TB and key informant interviews with their family members, health workers and KwaZulu-Natal Provincial Department of Health personnel. Results: Anti-MDR-TB treatment affects women’s sexuality, intimate relationships, family planning intentions and reproductive health. Some vulnerable women struggle to persevere on noxious and lengthy treatment regimes that affect their reproductive and psychological health. Women may skip doses or abandon treatment when high pill burdens and adverse events make intimate and sexual relations with male partners, on whom they may depend for their livelihoods, difficult. Conclusion: It is important to consider the effects of lengthy treatment on young people’s social and sexual lives and self-esteem when (re)designing MDR-TB counselling approaches. This paper advances an evidence-based treatment education and counselling strategy to contribute to improving MDR-TB treatment adherence and success.
Lived Experiences of Siblings of Individuals with Autism Spectrum Disorder in India: An Interpretative Phenomenological Analysis
Authors: Viswanathan Poornima , Kishore M. Thomas , Seshadri Shekhar P. 
Published: July 2021

Background: Autism spectrum disorder (ASD) can impact the individual and their families. The impact on siblings is unique because they evolve from being another child in the family to a future adult who can be a potential resource to the family in supporting a member with ASD. Since the quality of care and support can be affected by the lived experiences of the carer and there are not many studies on siblings, this study examined the lived experiences of siblings of individuals with ASD. Methods: Fourteen siblings of individuals with ASD, aged 15–36 years, were recruited from a tertiary hospital, schools, and private institutes. A semistructured interview schedule was used to explore the lived experiences. Interpretative phenomenological analysis (IPA) was used to identify the themes. Results: The themes based on IPA indicated that the siblings have very basic concerns like understanding the condition and complex issues such as coping, preparing for current and future roles, personal needs and expectations, need for a support system, and positive aspects of the sibling relationship. Nonetheless, the siblings minimized reporting their difficulties and focused more on the needs of the sibling with ASD. Conclusion: Siblings have diverse lived experiences, with a small element of positive experiences. Appropriate supports are needed to address the complexities of the lived experiences.
Impact of the COVID-19 pandemic on end of life care delivery in care homes: A mixed method systematic review
Authors: Spacey Adam , Porter Sam , Board Michele , Scammell Janet 
Published: July 2021

Background: Current evidence suggests that COVID-19 is having a negative impact on the delivery of end of life care in care homes around the world. There is a need to collate current evidence to provide a comprehensive overview to assess extent of the problem. Aim: To describe and evaluate the impact of the COVID-19 pandemic on end of life care delivery in care homes. Design: Systematic review and narrative synthesis of studies reporting qualitative and quantitative data. Data sources: The databases MEDLINE, psycINFO, SCOPUS and CINAHL were searched between December 2019 and March 2021. Results: Nine studies were included. For care home staff, challenges included significant increases in responsibility and exposure to death, both of which have taken an emotional toll. Results indicate that staff tended not to be offered adequate emotional support or afforded the time to grieve. For those receiving end of life care, results indicate that the end of life care that they tended to receive, especially in the form of advance planning, was disrupted by the pandemic. Conclusion: The effect of the pandemic has been to exacerbate existing problems in the provision of end of life care in care homes for both service providers and users, making that which was previously opaque starkly visible. Future research is needed to explore the effects of the pandemic and its management on those receiving end of life care in care homes and their significant others.