bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel scheme for defining the clinical implications of TP53 mutations in myeloid neoplasia
Authors: Bahaj Waled , Kewan Tariq , Gurnari Carmelo , Durmaz Arda , Ponvilawan Ben , Pandit Ishani , Kubota Yasuo , Ogbue Olisaemeka D. , Zawit Misam , Madanat Yazan , Bat Taha , Balasubramanian Suresh K. , Awada Hussein , Ahmed Ramsha , Mori Minako , Meggendorfer Manja , Haferlach Torsten , Visconte Valeria , Maciejewski Jaroslaw P.
Published: August 2023

Background

TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis.

Methods

We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely.

Results

Overall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases.

Conclusion

Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.
BEDwARS: a robust Bayesian approach to bulk gene expression deconvolution with noisy reference signatures
Authors: Ghaffari Saba , Bouchonville Kelly J. , Saleh Ehsan , Schmidt Remington E. , Offer Steven M. , Sinha Saurabh
Published: August 2023

Differential gene expression in bulk transcriptomics data can reflect change of transcript abundance within a cell type and/or change in the proportions of cell types. Expression deconvolution methods can help differentiate these scenarios. BEDwARS is a Bayesian deconvolution method designed to address differences between reference signatures of cell types and corresponding true signatures underlying bulk transcriptomic profiles. BEDwARS is more robust to noisy reference signatures and outperforms leading in-class methods for estimating cell type proportions and signatures. Application of BEDwARS to dihydropyridine dehydrogenase deficiency identified the possible involvement of ciliopathy and impaired translational control in the etiology of the disorder.
A syntelog-based pan-genome provides insights into rice domestication and de-domestication
Authors: Wu Dongya , Xie Lingjuan , Sun Yanqing , Huang Yujie , Jia Lei , Dong Chenfeng , Shen Enhui , Ye Chu-Yu , Qian Qian , Fan Longjiang
Published: August 2023

Background

Asian rice is one of the world’s most widely cultivated crops. Large-scale resequencing analyses have been undertaken to explore the domestication and de-domestication genomic history of Asian rice, but the evolution of rice is still under debate.

Results

Here, we construct a syntelog-based rice pan-genome by integrating and merging 74 high-accuracy genomes based on long-read sequencing, encompassing all ecotypes and taxa of Oryza sativa and Oryza rufipogon. Analyses of syntelog groups illustrate subspecies divergence in gene presence-and-absence and haplotype composition and identify massive genomic regions putatively introgressed from ancient Geng/japonica to ancient Xian/indica or its wild ancestor, including almost all well-known domestication genes and a 4.5-Mbp centromere-spanning block, supporting a single domestication event in main rice subspecies. Genomic comparisons between weedy and cultivated rice highlight the contribution from wild introgression to the emergence of de-domestication syndromes in weedy rice.

Conclusions

This work highlights the significance of inter-taxa introgression in shaping diversification and divergence in rice evolution and provides an exploratory attempt by utilizing the advantages of pan-genomes in evolutionary studies.
Promoter hypermethylation of neural-related genes is compatible with stemness in solid cancers
Authors: Idris Musa , Coussement Louis , Alves Maria M. , De Meyer Tim , Melotte Veerle
Published: August 2023

Background

DNA hypermethylation is an epigenetic feature that modulates gene expression, and its deregulation is observed in cancer. Previously, we identified a neural-related DNA hypermethylation fingerprint in colon cancer, where most of the top hypermethylated and downregulated genes have known functions in the nervous system. To evaluate the presence of this signature and its relevance to carcinogenesis in general, we considered 16 solid cancer types available in The Cancer Genome Atlas (TCGA).

Results

All tested cancers showed significant enrichment for neural-related genes amongst hypermethylated genes. This signature was already present in two premalignant tissue types and could not be explained by potential confounders such as bivalency status or tumor purity. Further characterization of the neural-related DNA hypermethylation signature in colon cancer showed particular enrichment for genes that are overexpressed during neural differentiation. Lastly, an analysis of upstream regulators identified RE1-Silencing Transcription factor (REST) as a potential mediator of this DNA methylation signature.

Conclusion

Our study confirms the presence of a neural-related DNA hypermethylation fingerprint in various cancers, of genes linked to neural differentiation, and points to REST as a possible regulator of this mechanism. We propose that this fingerprint indicates an involvement of DNA hypermethylation in the preservation of neural stemness in cancer cells.
Joint DNN partitioning and task offloading in mobile edge computing via deep reinforcement learning
Authors: Zhang Jianbing , Ma Shufang , Yan Zexiao , Huang Jiwei
Published: August 2023

As Artificial Intelligence (AI) becomes increasingly prevalent, Deep Neural Networks (DNNs) have become a crucial tool for developing and advancing AI applications. Considering limited computing and energy resources on mobile devices (MDs), it is a challenge to perform compute-intensive DNN tasks on MDs. To attack this challenge, mobile edge computing (MEC) provides a viable solution through DNN partitioning and task offloading. However, as the communication conditions between different devices change over time, DNN partitioning on different devices must also change synchronously. This is a dynamic process, which aggravates the complexity of DNN partitioning. In this paper, we delve into the issue of jointly optimizing energy and delay for DNN partitioning and task offloading in a dynamic MEC scenario where each MD and the server adopt the pre-trained DNNs for task inference. Taking advantage of the characteristics of DNN, we first propose a strategy for layered partitioning of DNN tasks to divide the task of each MD into subtasks that can be either processed on the MD or offloaded to the server for computation. Then, we formulate the trade-off between energy and delay as a joint optimization problem, which is further represented as a Markov decision process (MDP). To solve this, we design a DNN partitioning and task offloading (DPTO) algorithm utilizing deep reinforcement learning (DRL), which enables MDs to make optimal offloading decisions. Finally, experimental results demonstrate that our algorithm outperforms existing non-DRL and DRL algorithms with respect to processing delay and energy consumption, and can be applied to different DNN types.
Association of weight-adjusted-waist index with non-alcoholic fatty liver disease and liver fibrosis: a cross-sectional study based on NHANES
Authors: Hu Qinggang , Han Kexing , Shen Jiapei , Sun Weijie , Gao Long , Gao Yufeng
Published: August 2023

Aim

The purpose of this study was to explore the association of weight-adjusted-waist index (WWI) with non-alcoholic fatty liver disease (NAFLD) and liver fibrosis.

Methods

A cross-sectional study including 6587 participants was conducted in the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression was used to validate the association of WWI with NAFLD and liver fibrosis, and smoothed curve fitting and threshold effect models were used to validate non-linear relationships. Subgroup analyses were used to verify the stability of the relationship between the independent and dependent variables in different populations.

Results

There was a positive association of WWI with NAFLD and liver fibrosis. In the model adjusted for all covariates, the effect values of WWI with NAFLD and liver fibrosis were (OR = 3.44, 95% CI: 3.09–3.82) and (OR = 2.40, 95% CI: 2.05–2.79), respectively. This positive correlation became more significant as WWI increased when WWI was presented in quartiles (P for trend < 0.01). Smoothed curve fitting and threshold effects analysis suggested a non-linear correlation between WWI and NAFLD (LLR < 0.01), with the positive correlation between WWI and NAFLD becoming more significant when WWI was less than 11.44 [5.93 (95% CI: 5.04–6.98)]. However, there was a linear correlation between WWI and liver fibrosis (LLR = 0.291). When subgroup analyses were performed by indicators such as age, race and gender, we found that the positive association between WWI and the dependent variables (NAFLD and liver fibrosis) was more pronounced in white male participants aged < 40 years.

Conclusions

Among adults in the United States, WWI was positively associated with the prevalence of NAFLD and liver fibrosis. Participants with a WWI less than 11.44 should be cautious about the possibility of an increased risk of NAFLD development due to a higher WWI. Meanwhile, white males younger than 40 years of age should be more cautious about the higher risk of NAFLD and liver fibrosis that might be associated with an increased WWI.
COVID and depression among stratified population groups: a narrative review
Authors: Charul  , Raina Jyotdeep K. , Sharma Sourabh , Pal Shash , Dogra Vikas , Kumar Parvinder , Panjaliya Rakesh K.
Published: August 2023

The Covid-19 pandemic has impacted and infiltrated every aspect of our lives. Successive lockdowns, social distancing measures, and reduction in economic activity have developed a new way of living and, in many cases, tend to lead to depression. The initial strict lockdown for about 3 months and eventually for a few more months has imposed greater challenges on children and adolescents in terms of psychological problems and psychiatric disorders. Regardless of their viral infection status, many people have been affected by the psychosocial changes associated with the Covid-19 pandemic. In the present review, we have attempted to evaluate the impact of COVID on the mental health of people from different age groups and occupations. The present review has highlighted the need for taking effective measures by the stakeholder to cope with depression among human population groups worldwide.
Differences among feminist and non-feminist women on weight bias internalization, body image, and disordered eating
Authors: Martin-Wagar Caitlin A. , Attaway Sarah E. , Melcher Katelyn A.
Published: August 2023

Background

Research yields mixed results on whether feminist beliefs or self-identification are protective against body image disturbance and eating pathology in non-clinical populations. Further, no studies have examined feminism among those with diagnosed eating disorders. Additionally, previous studies have not examined the relationship between feminist identity and weight stigma. This study investigated these relationships and if there are differences in body image, eating pathology, and weight stigma among feminist identity types in women with eating disorders and college women using ANCOVAs.

Methods

Participants completed self-report measures and were women with eating disorders (N = 100) and college women (N = 240).

Results

Sixty-four percent of the women with eating disorders and 75.8% of the college women identified as a feminist. An independent samples t-test found a significantly higher weight bias internalization in the clinical eating disorder sample than in the college women sample. No significant interactions were found between sample type and feminist identity for body image or weight bias internalization. Results were consistent when using a dichotomous feminist identity item and a seven-item continuous feminist identity item.

Conclusions

Despite the clear impacts of the intersection of weight status and gender, results from this study suggest that identifying as a feminist is not sufficient to combate weight stigma. Findings highlight the need for further research investigating weight bias internalization within eating disorder prevention efforts and interventions.
The impact of negative and positive affectivity on the relationship between work-related psychological factors and work engagement in Japanese workers: a comparison of psychological distress
Authors: Fukuzaki Toshiki , Iwata Noboru
Published: August 2023

Background

A previous study has shown that Japanese individuals generally exhibit behavior that suppresses the expression of positive emotions, which are strongly affected by affectivity traits. In the present study, to clarify the relationship between affectivity traits and work engagement (WE) or work-related psychosocial factors among Japanese workers, we compared it to the association between psychological distress and these same factors.

Methods

A total of 1,000 full-time Japanese regular workers responded to an online survey that measured demographic variables, negative and positive affectivity, job demands and resources, WE, and psychological distress. A hierarchical multiple regression analysis was conducted separately, which used WE and psychological distress as dependent variables.

Results

The proportion of variance explained by negative and positive affectivity was lower for WE than for psychological distress. However, the proportion of variance defined by job demands and resources was higher for WE than for psychological distress. The proportion of variance explained by all variables for negative and positive affectivity and job demands and resources, and their interactions was approximately equal for WE and psychological distress.

Conclusion

These results emphasize when researchers aim to evaluate the change of psychosocial factors in the workplace, such as improving the workplace environment among Japanese workers, it might be beneficial to measure positive indicators in addition to negative indicators. Furthermore, enriching job resources would be effective in improving WE and alleviating psychological distress.
Impact of organic fertilization by the digestate from by-product on growth, yield and fruit quality of tomato (Solanum lycopersicon) and soil properties under greenhouse and field conditions
Authors: Li Faqinwei , Yuan Yongheng , Shimizu Naoto , Magaña Jorge , Gong Pengxuan , Na Risu
Published: August 2023

Background

The application of organic fertilizer is a sustainable approach to maintain soil fertility in agricultural crop production. In contrast to other organic fertilizers, the digestate from by-products of anaerobic digestion has not been well characterized in terms of its agronomic properties. In this study, different fertilization treatments were investigated to evaluate their impacts on growth, yield and fruit quality of tomatoes and on soil properties under greenhouse and field conditions. The experiments comprised a control (unfertilized) and three treatments with the same nitrogen dose: chemical fertilizer, digestate from by-product (organic fertilizer) and digestate combined with chemical fertilizer.

Results

The results showed that the application of digestate significantly increased the growth and fruit quality of tomato including height, stem diameter, leaf chlorophyll content index, and photosynthetic rate of tomato plant and sugar–acid ratio, protein content, and ascorbic acid content of the fruit. The nitrate contents in tomato fruit were lower in the digestate treatment and digestate combined with chemical fertilizer treatment than in the chemical fertilizer. The digestate combined with chemical fertilization resulted in the greatest increase in tomato yield, up to 26.29% and 10.78% higher than that in the chemical fertilizer treatment under field and greenhouse conditions, respectively. Moreover, fertilization with digestate treatment and digestate combined with chemical fertilizer treatment increased soil fertility, including soil nitrogen and carbon contents, and enhanced soil enzyme activities under both field and greenhouse conditions. In addition, the growth, yield, and fruit quality of tomato were significantly correlated with soil chemical characteristics and soil enzyme activities.

Conclusions

The effects of digestate treatments to maintain a stable tomato yield and improve fruit quality may be due to the enhanced soil enzymatic activities and chemical properties. These results suggest that the use of digestate as a full or partial replacement for chemical fertilizer could improve the growth and fruit quality of tomato, maintain the yield, and reduce the use of inorganic fertilizers in tomato production.

Graphical Abstract
Impact of the fungal pathogen Fusarium oxysporum on the taxonomic and functional diversity of the common bean root microbiome
Authors: Mendes Lucas William , Raaijmakers Jos M , de Hollander Mattias , Sepo Edis , Gómez Expósito Ruth , Chiorato Alisson Fernando , Mendes Rodrigo , Tsai Siu Mui , Carrión Victor J
Published: August 2023

Background

Plants rely on their root microbiome as the first line of defense against soil-borne fungal pathogens. The abundance and activities of beneficial root microbial taxa at the time prior to and during fungal infection are key to their protective success. If and how invading fungal root pathogens can disrupt microbiome assembly and gene expression is still largely unknown. Here, we investigated the impact of the fungal pathogen Fusarium oxysporum (fox) on the assembly of rhizosphere and endosphere microbiomes of a fox-susceptible and fox-resistant common bean cultivar.

Results

Integration of 16S-amplicon, shotgun metagenome as well as metatranscriptome sequencing with community ecology analysis showed that fox infections significantly changed the composition and gene expression of the root microbiome in a cultivar-dependent manner. More specifically, fox infection led to increased microbial diversity, network complexity, and a higher proportion of the genera Flavobacterium, Bacillus, and Dyadobacter in the rhizosphere of the fox-resistant cultivar compared to the fox-susceptible cultivar. In the endosphere, root infection also led to changes in community assembly, with a higher abundance of the genera Sinorhizobium and Ensifer in the fox-resistant cultivar. Metagenome and metatranscriptome analyses further revealed the enrichment of terpene biosynthesis genes with a potential role in pathogen suppression in the fox-resistant cultivar upon fungal pathogen invasion.

Conclusion

Collectively, these results revealed a cultivar-dependent enrichment of specific bacterial genera and the activation of putative disease-suppressive functions in the rhizosphere and endosphere microbiome of common bean under siege.
Clinical characteristics of patients with suspected Alzheimer’s disease within a CSF Aß-ratio grey zone
Authors: Yosypyshyn Dariia , Kučikienė Domantė , Ramakers Inez , Schulz Jörg B. ,   for the Alzheimer’s Disease Neuroimaging Initiative, Reetz Kathrin , Costa Ana Sofia
Published: August 2023

Background

The AT(N) research framework for Alzheimer's disease (AD) remains unclear on how to best deal with borderline cases. Our aim was to characterise patients with suspected AD with a borderline Aß1-42/Aß1-40 ratio in cerebrospinal fluid.

Methods

We analysed retrospective data from two cohorts (memory clinic cohort and ADNI) of patients (n = 63) with an Aß1-42/Aß1-40 ratio within a predefined borderline area—Q1 above the validated cut-off value(grey zone). We compared demographic, clinical, neuropsychological and neuroimaging features between grey zone patients and patients with low Aß1-42 (normal Aß ratio but pathological Aß1-42, n = 42) and patients with AD (pathological Aß, P-Tau, und T-Tau, n = 80).

Results

Patients had mild cognitive impairment or mild dementia and a median age of 72 years. Demographic and general clinical characteristics did not differ between the groups. Patients in the grey zone group were the least impaired in cognition. However, they overlapped with the low Aß1-42 group in verbal episodic memory performance, especially in delayed recall and recognition. The grey zone group had less severe medial temporal atrophy, but mild posterior atrophy and mild white matter hyperintensities, similar to the low Aß1-42 group.

Conclusions

Patients in the Aß ratio grey zone were less impaired, but showed clinical overlap with patients on the AD continuum. These borderline patients may be at an earlier disease stage. Assuming an increased risk of AD and progressive cognitive decline, careful consideration of clinical follow-up is recommended when using dichotomous approaches to classify Aß status.
Hydraulic fracturing-induced microseismicity controlled by rock brittleness and natural fractures in Tongren, Guizhou, China
Authors: Li Dewei , Zheng Jing , Peng Suping , Yang Ruizhao , Meng Lingbin , Shi Weijian
Published: August 2023

Hydraulic fracturing-induced microseismicity has drawn public attention in recent years. However, understanding the behavior of hydraulic fracture is limited due to the complex relationship between microseismicity and various geologic conditions. To further understand this question, we conduct a study to detect and locate hydraulic fracturing-induced microseismicity at a shale gas production site in Tongren, Guizhou, China. We investigate the relationship between their distribution and two important geologic factors: the brittleness index (BI) of rocks and the distribution of natural fractures. With the aid of a 3D active seismic survey, we first calculate the BI of rocks in the hydraulic fracturing region using Young’s modulus and Poisson’s ratio, compared with the locating result of fracturing-induced microseismicity, which indicates that most of the events are distributed in the area with higher BI. We then delineate natural fractures using the ant-tracking method of the 3D seismic attribute. The microseismic location is consistent with the region of natural fractures. Based on our findings, we suggest that the spatial distribution of induced microseismicity is highly controlled by the brittleness of rocks and the distribution of natural fractures in this region. This research provides insights into the factors controlling hydraulic fracturing-induced microseismicity and enhances our understanding of the complex interplay between geologic conditions and the behavior of hydraulic fractures.
Opportunities and Challenges of Synthetic Data Generation in Oncology
Authors: Jacobs Flavia , D'Amico Saverio , Benvenuti Chiara , Gaudio Mariangela , Saltalamacchia Giuseppe , Miggiano Chiara , De Sanctis Rita , Della Porta Matteo Giovanni , Santoro Armando , Zambelli Alberto
Published: August 2023

Widespread interest in artificial intelligence (AI) in health care has focused mainly on deductive systems that analyze available real-world data to discover patterns not otherwise visible. Generative adversarial network, a new type of inductive AI, has recently evolved to generate high-fidelity virtual synthetic data (SD) trained on relatively limited real-world information. The AI system is fed with a collection of real data, and it learns to generate new augmented data while maintaining the general characteristics of the original data set. The use of SD to enhance clinical research and protect patient privacy has drawn a lot of interest in medicine and in the complex field of oncology. This article summarizes the main characteristics of this innovative technology and critically discusses how it can be used to accelerate data access for secondary purposes, providing an overview of the opportunities and challenges of SD generation for clinical cancer research and health care.
LookUpTrials: Assessment of an artificial intelligence-powered mobile application to engage oncology providers in clinical trials.
Authors: Hung Kin Wai (Tony) , Dunn Lara , Sherman Eric Jeffrey , Ho Alan Loh , Fetten James Vincent , Michel Loren S. , Kriplani Anuja , Baxi Shrujal S. , Wong Winston , Sanford Rachel Ann , Wong Richard J. , Lee Nancy Y. , Kuperman Gilad , Mao Jun J. , Pfister David G.
Published: August 2023

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Background: Clinical trials are integral to cancer care but face frequent accrual challenges as they grow numerous and complex. Artificial intelligence (AI) technologies can cognitively aid oncology providers, but few have rigorously been evaluated or optimally integrated into clinical workflow. We developed an AI-powered mobile application, LookUpTrials, to support oncology providers in facilitating point-of-care access to relevant information on cancer clinical trials. This study examines user engagement of LookUpTrials among oncology providers. Methods: LookUpTrials functions as a search engine for clinical trials. Unlike traditional trial registries, LookUpTrials provides an open forum, similar to a social media platform, to allow users to update information (i.e., trial availability) and share knowledge (i.e., clinical experience) about clinical trials. Additionally, LookUpTrials leverage Al technologies supported by Apple Inc. and ChatGPT to assist with summary and search queries. Similar applications exist, but few support real-time update, editable by clinical trial teams. On Feb 27th, 2022, we piloted LookUpTrials in the Head and Neck and Breast medical oncology services at the Memorial Sloan Kettering Cancer Center (MSK). Leveraging Google Firebase and Apple Analytics, LookUpTrials prospectively auto-captured user engagement measures. Measurement included: 1) sessions: instances when users opened app or viewed an app screen; 2) engaged sessions: sessions that lasted longer than 10 seconds or had 2 or more screen views; and 3) engagement time: time that app ran in the foreground. We applied market segmentation and descriptive statistics to analyze the measures. Results: In 2022, LookUpTrials received 166 downloads, the majority within the United States (73%), a few unknown (7%), and others across 8 countries, including China (9%), Ukraine (5%), Egypt (1%), France (1%), Morocco (1%), Switzerland (1%), Turkey (1%), and the United Kingdom (1%). Within the MSK pilot, LookUpTrials provided information on over 80 trials, including trials on breast cancer, head and neck cancers, thyroid cancers, salivary gland cancers, and non-melanoma skin cancers. Among 115 active users (72% of downloads), the application recorded 1,115 engaged sessions (68% of sessions), averaging 10 engaged sessions per user and an engagement time of 39 minutes and 8 seconds. Conclusions: LookUpTrials demonstrated promising user engagement among oncology providers. As the number and complexity of cancer clinical trials expand, future studies are needed to evaluate the optimal process to integrate LookUpTrials into cancer care delivery and to understand its effects in supporting providers in trial accrual.
Real-time, multiplexed rendering of lymphoma diagnostic panels from unstained tissue sections using virtual staining.
Authors: Kobayashi Hirofumi , Kallen Michael E , Kozikowski Raymond , de Haan Kevin , Fang Zihang , Alexanian Serge , Carvalho L. a. V. , Rivenson Yair
Published: August 2023

115

Background: Lymphoproliferative disorders are complex, heterogeneous diseases with an ever expanding array of subtypes and variants requiring stepwise assay approach to arrive at a precise diagnosis. While extensive characterization of lesional cells and the microenvironment (TME) via immunophenotyping and genotyping remains the gold standard, a full workup may be unachievable due to limited input tissue, turnaround time pressure, or unavailability of particular markers in-house. Even when available, the interpretation of large numbers of markers by pathologists is limited by the ability to mentally spatially align markers by recall-superimposition of single-plex markers, limiting the discovery of patterns relevant for novel treatments strategies. Here we present a deep-learning based virtual staining method which transforms a single unstained tissue section into a panel of perfectly aligned virtual immunohistochemical (IHC) stained images. Methods: 4um unstained sections were cut from 30 formalin-fixed paraffin-embedded blocks. Using a standard commercial slide scanner (Axio Scan.Z1, Zeiss), autofluorescence images were captured from unstained sections and paired with brightfield images captured from the same sections after chemical staining with H&E or various IHC stains of interest. The virtual staining was performed by a deep neural network trained as a conditional GAN using accurately co-registered patches of paired images . The training dataset comprised seven types of lymphoma plus benign lymphoid tissues. Results: We successfully created models for virtual CD3, CD8, CD20 and CD30 IHC stains as well as H&E. Analysis by board certified pathologists confirmed consistent and accurate results between virtual and IHC stained slides in a range of lymphomas and reactive lymphoid tissue. We quantitatively evaluated the co-expression of CD3/CD8 and the spatial distribution of all four markers in eight holdout slides. We demonstrated that our virtual multiplex IHC staining achieves comparable performance for WSI scoring and cellular localization with actual staining across lymphoma types. Conclusions: We present the feasibility of spatially aligned, rapid virtual H&E and IHC staining of four different markers from single, label-free autofluorescence images using deep-learning techniques. To the best of our knowledge, this is the first report of a panel of virtual IHC stains, perfectly aligned and with overlaid H&E structural context, for analysis of neoplastic and reactive lymphoid tissues. Our technique provides an opportunity for a rapid, comprehensive histopathology and immunophenotyping workflow. Multiplex virtual staining greatly expands diagnostic and discovery opportunities: high accuracy TME profiling, seamless downstream computational image analysis, and screening of large biomarker pools in retrospective analysis of clinical trials.
The effect of corticosteroid on immunogenicity of SARS-CoV-2 vaccines in solid cancer patients.
Authors: Samdaengpan Chayanee , Sungkasubun Prakongboon , Chaiwiriyawong Worawit , Siripaibun Jomtana , Phanthunane Chumut , Tantiyavarong Walaipan , Lamlertthon Wisut , Ungtrakul Teerapat , Tawinprai Kriangkrai , Limpawittayakul Piyarat
Published: August 2023

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Background: Corticosteroids are known to diminish immune response ability, which is generally used in routine pre-medication for chemotherapy. The intersecting of timeframe between the corticosteroid’s duration of action and peak COVID-19 vaccine efficacy could impair vaccine immunogenicity. Thus, inquiring about corticosteroids affecting the efficacy of vaccines, a dose of corticosteroids, and optimal timing of vaccination to promote effective immunity in this population is needed. Methods: This was a prospective longitudinal observational cohort study that enrolled solid cancer patients classified into dexamethasone and non-dexamethasone receiving groups. All participants were immunized with two doses of ChAdOx1 nCoV-19 or CoronaVac vaccines. This study's purpose was to compare corticosteroid's effect on immunogenicity responses to the SARS-CoV-2 S protein in solid cancer patients following two doses of COVID-19 vaccine in the dexamethasone and non-dexamethasone group. Secondary outcomes included the post-immunization anti-S IgG seroconversion rate, the association of corticosteroid dosage, time duration and immunogenicity level. Results: Among the 161 enrolled solid cancer patients, 71 and 90 were in the dexamethasone and non- dexamethasone groups, respectively. The median anti-S IgG titer after COVID-19 vaccination in the dexamethasone group was lower than non- dexamethasone group with a statistically significant difference (47.22 vs 141.09 U/ml, p = 0.035). The anti-S IgG seroconversion rate was also significantly lower in the dexamethasone group than in the non- dexamethasone group (93.83% vs 80.95% p = 0.023). The lowest median anti-SARS-CoV-2 IgG titer level at 7.89 AU/ml showed in patients with the highest dose of steroid group (37 mg or more of dexamethasone) and patients who were injected with COVID-19 vaccines on the same day of receiving dexamethasone, 25.41 AU/ml. Conclusions: Solid cancer patients vaccinated against COVID-19 while receiving dexamethasone had lower immunogenicity responses than those who got vaccines without dexamethasone, regardless of active cancer treatment types.The direct association between immunogenicity level and steroid dosage, as well as length of duration from vaccination to dexamethasone was observed. Clinical trial information: TCTR20221001004 .
Integrating multi-omics features for blood-based multi-cancer early detection.
Authors: Mao Mao , Li Shiyong , Ren Qingqi , Luan Yi , Liang Weijie , Geng Shuaipeng , Zhong Guolin , Zhu Dandan , Chang Yinyin , Wu Wei , Zhang Yingying , Zhang Linfeng , Wang Yan , Feng Yumin , Wei Bing , Ma Jie , Duan Chaohui , Long Guanghui
Published: August 2023

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Background: The current standard-of-care cancer screening paradigm is constrained to just a few cancer types and has challenges in patient compliance due to the invasive procedures endured from the tests. Recently studies have demonstrated that blood-based multi-cancer detection (MCED) approaches may hold promise for identifying asymptomatic cancer patients from the general population. However, most studies only exploit a single aspect of cancer hallmarks which is challenging for the biological reasons since cancer is a heterogenous disease with a wide spectrum of pathological and clinical behaviors. Methods: Here we report SeekInCare, a CE-IVD Mark MCED test, based on a novel multi-dimensional cancer risk score (CRS) model incorporating copy number aberrations, fragment size, end motifs and oncogenic viruses via shallow whole genome sequencing (sWGS) from cell-free DNA (cfDNA), and seven common tumor markers in a single 8ml blood draw. Results: Our research cohort consisted of 898 healthy subjects and 615 stage I-IV cancer patients that covered eight common cancers and 19 uncommon cancer types. The CRS model identified 427 cancer patients with 69.4% sensitivity at 98.0% specificity, resulting in an AUC (area under the curve) of 0.926. The sensitivities were 50.3%, 64.0%, 73.8% and 86.2% in stage I, II, III and IV cancers respectively. The sensitivities of eight common cancer types, breast, stomach, lung, colorectum, lymphoma, liver, pancreas and leukemia, were 45.1%, 50.0%, 63.4%, 69.4%, 70.5%, 81.4%, 82.4% and 90.9% respectively. We also prospectively evaluated SeekInCare in a real-world cohort consisting of 1212 subjects who received the test as a LDT (laboratory developed test) (median follow-up time: 753 days, range: 78~1669 days). 13 out of 18 cancer cases were detected while 46 subjects tested positive but without cancer. Thus, SeekInCare achieved 72.2% sensitivity, 96.1% specificity, 22.0% PPV and 99.6% NPV in the real-world cohort. Conclusions: In this study, we provided a non-invasive MCED test (SeekInCare) based on the multi-omics and multi-dimensional features. The case-control study demonstrated that SeekInCare could detect >20 cancer types with 69.4% sensitivity at 98.0% specificity. The outstanding real-world performance of SeekInCare warrants future investigation of its clinical utility and health economics as a mass cancer screening test in average-risk populations.
Pattern of mismatch repair proteins in colorectal cancer patients in tertiary cancer center.
Authors: Kale Ajinkya Shantaram , Saklani Avanish
Published: August 2023

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Background: Prevalence of MSI high in colorectal cancer patients in India has been debated in previous literature. Microsatellite instability pathway is one of the major pathways in carcinogenesis of colorectal carcinoma. MSI status has paramount significance in therapeutic and prognostic aspects of colorectal cancer management. MSI status can be evaluated by presence or absence of mismatch repair proteins. Aims & objectives: we aimed to determine the prevalence of MSI high in colorectal carcinoma and pattern of mismatch repair proteins. Methods: This was retrospective study which included consecutively operated colorectal carcinoma patients from 01 may 2022 to 31 December 2022 in our institute. Immunohistochemistry with four mismatch repair (MMR) proteins; MLH1, MSH2, MSH6, and PMS2 was performed. Correlation with various clinical and histopathological features was done. Results: total 296 colorectal carcinoma patients were included in our study. Fourty one (13.85%) patients were MSI high. Most common pattern of MMR protein expression loss was dual loss of MLH1 and PMS2 (n=18). Most common single protein loss was PMS2 (n=22). Most common location of tumor in MSI high patients was the right colon. (n=20). Out of 153 carcinoma rectum patients only five patients were MSI high. Conclusions: The study shows that prevalence of MSI high is more common in right colon cancer. Prevalence of MSI high is very low in carcinoma rectum. We discuss and compare our results with previous studies.
A novel non-invasive multi-target stool DNA methylation assay for early detection of gastrointestinal cancers.
Authors: Sun Li-Yue , Shen Ju , Zhong Yu-Yun , Yang Jiao-Jiao , Jiang Yu-Ying , Cheng Yan-Jun , Wang Xi-Ying , Wang Rui-Qi , Liu Fei , Liu Fang , Chen Meng-Jin , Ling Xiao-Mei , Wen Jie-Lun , Wang Fang , Zhang Xu-Hui
Published: August 2023

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Background: Gastrointestinal (GI) cancers accounts for one-third of the world’s cancer burden. Liquid biopsies such as SEPT9 methylation and Cologuard have been approved by the Food and Drug Administration for early detection of colorectal cancer (CRC), but not for other GI cancers. In addition, although CancerSEEK can be employed in the detecting of multiple GI cancers, it has low sensitivity and without localization. Stool is a promising sample for GI cancer detection because it contains the host’s exfoliated cells and circulating free DNA derived from GI cancer cells. Thus, we aimed to develop a sensitive and non-invasive multi-target stool DNA methylation test for early detection and localization of GI cancers. Methods: We prospectively enrolled 124 patients histologically diagnosed with GI cancer without treatment and 92 healthy controls who underwent GI cancer-related examinations every 3 years. Stool DNA was extracted from the supernatant of a mixture containing 5 g fresh stool and 25 ml preservative solution using the stool DNA extraction kit. The samples were subjected to bisulfite conversion using the EZ DNA Methylation Kit, and the treated with stool DNA multi-target methylation assay kit to detect the methylation levels of 3 target regions of stool DNA (PDX1, COL4A2-1, and FGF5) with qPCR. Based on the guidelines of the protocol, positive result was defined as ΔCt value (ΔCt = Ct (target gene) - Ct (GAPDH))＜10 for any three genes. Multiple logistic regression (MLR) models for single GI cancers were constructed including the ΔCt value of each gene to adjust for tissue of origin (TOO) of GI cancers. This study was approved by the Clinical Research Ethics Committee of Guangdong Second Provincial General Hospital (2021-KZ-138-03). Results: Overall, 98 of 124 patients (79%) tested positive, and 88 of 92 healthy controls (96%) tested negative. For each GI cancer type, the positivity rates were 71%, 83%, 75%, 81% and 91% for CRC (24/34), gastric cancer (GC, 19/23), esophageal cancer (EC, 18/24), pancreatic cancer (PC, 17/21) and ampullary cancer (AC, 20/22), respectively. Interestingly, among 4 positive healthy controls, 3 were diagnosed as advanced adenomas and one case was a pregnant woman. For the MLR model, the sensitivity of CRC was 88% (30/34), that of GC was 91% (21/23), EC was 88% (21/24), PC was 90% (19/21), and AC was 95% (21/22). Conclusions: The multi-target stool DNA methylation assay allowed early and accurate detection and identification of tissue of origin of GI cancers. [Table: see text]
Gut microbiome to predict durable response to immunotherapy in patients with hepatocellular carcinoma.
Authors: Zhao Caining , Liang Zhibing , Xu Wanli , Chen Wenqi , Li Shanshan , Kong Feng-Ming Spring
Published: August 2023

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Background: Patients with hepatocellular carcinoma (HCC) can hardly benefit from immunotherapy (IO); however, few patients develop durable responses to IO (long-responder, LR). Gut microbiota implicate IO response in multiple cancers, while its characteristics in LRs of IO has not been well sketched. With these motivations, we applied metagenomics to comprehensively unveil intestinal flora profiles in LRs, and compare with less responders to investigate its potential in response prediction. Methods: Advanced HCC patients treated with anti-PD-1 with/without anti-CTLA-4 fall into 3 distinct subgroups: non-responders (NRs) presenting early disease progression within 6 months, long responders (LRs) who achieve durable disease control with a minimum of 12 months, and the remaining short responders (SRs). Fresh stool samples were collected for metagenomic sequencing at least 12 months after initiation of a variety of immunotherapy regimens in LRs, while samples were collected within 6 months of IO treatment for NRs and SRs. Metagenome profiles were annotated using Kraken, and significant differences were revealed by Lefse analysis. Results: A total of 66 patients with advanced HCC who received IO first time were enrolled, 38 patients were evaluated as LRs, 8 as SRs, and 20 as NRs. Metagenome profiling unveiled significant association in its diversity and composition with clinical response. The β-diversity increased gradually as the treatment response getting better (p < 0.001). The β-diversity was significantly lower in NRs in comparison with SRs (p < 0.05) and LR (p < 0.001), while there was no significance between SRs and LRs. Significant higher abundance of Clostridium_butyricum was observed in LRs compared with NRs. Moreover, anabolic pathways like fatty acid biogenesis were significantly enriched in LRs. Conclusions: Gut metagenomic diversities and profiles were related with IO response in advanced HCC patients, which could be potential prediction biomarkers of IO durable benefits. The enrichment of probiotics like Clostridium_butyricum and its derived fatty acid have a mechanistic impact on higher antitumor immunity, which need further verification study.
A comparative study of the effectiveness of multiagent platinum based concurrent plus adjuvant versus conventional single agent platinum based concurrent chemotherapy in carcinoma cervix.
Authors: Shah Salman Khurshid
Published: August 2023

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Background: Cervical cancer is the 4th most common cancer in females worldwide. Combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (BT) with concurrent chemotherapy is the current standard of care for locally advanced cervical cancer. Even though the trials used separate combinations, the common end point suggested that platinum is single most effective chemotherapy agent. Since the latest data on platinum based polychemotherapy globally indicates its overall benefit, further trials are required to determine what regimens would be ideal for treatment of cervical cancer with maximum benefits and least toxicities. Objectives: 1. To compare the response to doublet polychemotherapy with conventional chemotherapy in carcinoma cervix treated with chemoradiation. 2. To compare toxicity profile of doublet polychemotherapy with conventional chemotherapy. Methods: 66 patients of carcinoma cervix were enrolled in this study and were randomized to two arms. Arm A (n=34) was the experimental arm and the patients received concurrent weekly cycles of cisplatin(40mg/m2) plus gemcitabine (125mg/m2) along with EBRT followed by HDR brachytherapy, after 2-3 weeks of which they received 2 adjuvant cycles (21 days each) of gemcitabine (1000mg/m2 on Day1 and Day 8) and cisplatin (50mg/m2 on Day 1). Arm B(n=32) was the control arm and the patients received standard treatment which is concurrent weekly cycles single agent cisplatin(40mg/m2) with EBRT followed by HDR brachytherapy. EBRT doses ranged from 45Gy to 50.4 Gy at 1.8 to 2 Gy per fraction .BT application was either ICBT or ISBT depending on tumour response to EBRT, assessed by MRI. Patients were followed up for response assessment and late toxicities within 6 months of completion of treatment by clinical examination and MRI which was reported using RECIST 1.1 criteria. Results: On 6 month follow up MRI, number of patients achieving CR was 10% higher in the experimental arm (Arm A, n=33;97.06%) than the control arm (Arm B, n=28;87.5%).PR was seen in 2 patients, both from Arm B. Of the 3 patients presenting with PD at follow up 1 belonged to Arm A and 2 to Arm B (2.94% vs 6.25%). On pre-brachytherapy MRIs, the size reduction was better in Arm A and this reduction allowed a majority of patients in said arm to undergo ICBT instead of ISBT. The number of patients achieving >50% reduction post EBRT was 40% higher in Arm A. Acute GI and Hematological toxicities were seen in both arms but were higher in Arm A. as was Grade 3 neutropenia. Late toxicities were similar in both arms. Conclusions: The study concluded that the use of multiagent platinum-based chemotherapy in concurrent plus adjuvant setting can be advantageous. Improved tumour reduction can be achieved & disease can be made more amenable for ICBT. The accompanying toxicities were transient and clinically manageable.