bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital Reconstructions Using Linear Regression: How Well Can It Estimate Missing Shape Data from Small Damaged Areas?
Authors: Bucchi Ana , Del Bove Antonietta , López-Lázaro Sandra , Quevedo-Díaz Fernanda , Fonseca Gabriel M.
Published: November 2022

Skeletal remains analyzed by anthropologists, paleontologists and forensic scientists are usually found fragmented or incomplete. Accurate estimations of the original morphologies are a challenge for which several digital reconstruction methods have been proposed. In this study, the accuracy of reconstructing bones based on multiple linear regression (RM) was tested. A total of 150 digital models from complete zygomatics from recent past populations (European and African American) were studied using high-density geometric morphometrics. Some landmarks (i.e., 2, 3 and 6) were coded as missing to simulate incomplete zygomatics and the missing landmarks were estimated with RM. In the zygomatics, this simulated damage affects a few square centimeters or less. Finally, the predicted and original shape data were compared. The results indicate that the predicted landmark coordinates were significantly different from the original ones, although this difference was less than the difference between the original zygomatic and the mean zygomatic in the sample. The performance of the method was affected by the location and the number of missing landmarks, with decreasing accuracy with increasing damaged area. We conclude that RM can accurately estimate the original appearance of the zygomatics when the damage is small.
Genetic Stability Assessment of Six Cryopreserved Strawberry (Fragaria × ananassa Duch.) Accessions by Phenotypic and Molecular Studies
Authors: Bae Jinjoo , Choi Yunseo , Song Jae-Young , Lee Jung-Ro , Yoon Munsup , Lee Young-Yi
Published: November 2022

For the long-term preservation of genetic resources, cryopreservation techniques have been developed for strawberry germplasm, mainly using in vitro-grown shoot tips. In this study, genetic stability was tested under greenhouse conditions for six strawberry accessions (IT232511, PHS0132, IT245810, IT245830, IT245852, and IT245860) derived from the following procedures: (1) conventional propagation (GH: greenhouse maintained); (2) in vitro propagation (TC: tissue culture); (3) pretreatment before cryopreservation (−LN: non-liquid nitrogen exposure); and (4) cryopreservation (+LN: liquid nitrogen exposure). To test the performance of phenotypic traits, we measured six vegetative and five fruit traits. There were no distinct differences in most of the characteristics, but a few traits, such as sugar content and pH of fruits in three accessions, showed higher values in +LN compared to GH. However, the differences disappeared in the first runner generation. To test genetic variations, a total of 102 bands were generated by twelve inter simple sequence repeat (ISSR) primers. A few polymorphic bands were found only in plants derived from TC of IT245860, which was not cryopreserved. The sequencing analysis of four polymorphic bands produced by ISSR_15 showed that none of these sequences matched the characterized genes in NCBI. Phenotypic abnormality was not observed across all plants. This study indicates that cryopreserved plants of the six strawberry accessions are phenotypically and genetically stable. Therefore, the results of this study can help to implement cryobanking of strawberry germplasm.
Ribose Intake as Food Integrator: Is It a Really Convenient Practice?
Authors: Moschini Roberta , Balestri Francesco , Cappiello Mario , Signore Giovanni , Mura Umberto , Del-Corso Antonella
Published: November 2022

Reports concerning the beneficial effects of D-ribose administration in cardiovascular and muscle stressful conditions has led to suggestions for the use of ribose as an energizing food supplement for healthy people. However, this practice still presents too many critical issues, suggesting that caution is needed. In fact, there are many possible negative effects of this sugar that we believe are underestimated, if not neglected, by the literature supporting the presentation of the product to the market. Here, the risks deriving from the use of free ribose as ATP source, forcing ribose-5-phosphate to enter into the pentose phosphate pathway, is emphasized. On the basis of the remarkable glycation capacity of ribose, the easily predictable cytotoxic effect of the molecule is also highlighted.
Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer
Authors: Henriksson Sofia , Calderón-Montaño José Manuel , Solvie Daniel , Warpman Berglund Ulrika , Helleday Thomas
Published: November 2022

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras-expressing or -transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Several oncogenes induce replication stress, resulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment causes toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overexpressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but not by nucleoside supplementation. We conclude that the molecular toxicological mechanisms of how TH588 and TH1579 kill c-Myc overexpressing cells have several components and involve MTH1-independent proteasomal degradation of c-Myc itself, c-Myc-driven transcription and CDK activation.
Profiles of Metabolic Genes in Uncaria rhynchophylla and Characterization of the Critical Enzyme Involved in the Biosynthesis of Bioactive Compounds-(iso)Rhynchophylline
Authors: Yang Mengquan , Yao Bowen , Lin Rongmei
Published: November 2022

Rhynchophylline (RIN) and isorhynchophylline (IRN), two of the representative types of indole alkaloids, showed the unique spiroindole structures produced in Uncaria rhynchophylla. As the bioactive constituent of U. rhynchophylla, IRN has recently drawn extensive attention toward antihypertensive and neuroprotective activities. Despite their medicinal importance and unique chemical structure, the biosynthetic pathways of plant spiroindole alkaloids are still largely unknown. In this study, we used U. rhynchophylla, extensively used in traditional Chinese medicine (TCM), a widely cultivated plant of the Uncaria genus, to investigate the biosynthetic genes and characterize the functional enzymes in the spiroindole alkaloids. We aim to use the transcriptome platform to analyse the tissue-specific gene expression in spiroindole alkaloids-producing tissues, including root, bud, stem bark and leaf. The critical genes involved in the biosynthesis of precursors and scaffold formation of spiroindole alkaloids were discovered and characterized. The datasets from this work provide an essential resource for further investigating metabolic pathways in U. rhynchophylla and facilitate novel functional enzyme characterization and a good biopharming approach to spiroindole alkaloids.
Pseudocholinesterase as a Biomarker for Untreated Wilson’s Disease
Authors: Hefter Harald , Arslan Max , Kruschel Theodor S. , Novak Max , Rosenthal Dietmar , Meuth Sven G. , Albrecht Philipp , Hartmann Christian J. , Samadzadeh Sara
Published: November 2022

The aim of this study was to demonstrate that pseudocholinesterase (CHE) serum level is a useful diagnostic biomarker for untreated Wilson’s disease (WD). Between 2013 and 2019, about 75 patients were referred to the outpatient department of the University of Düsseldorf with suspected Wilson’s disease. In 31 patients with suspected Wilson’s disease (WD-SUS-group), WD was excluded by means of investigations other than analysis of blood and urine. A total of 27 parameters of blood and urine in these 31 patients were compared to those of 20 de novo patients with manifest WD (WD-DEF-group), which parameter showed the highest significance level of difference between the WD-DEF-group and the WD-SUS-group. Thereafter, receiver operating characteristics (ROC-curves) were analyzed to evaluate which parameter showed the largest area under the curve (AUC) to detect WD. Finally, a logistic regression analysis was performed to analyze which combination of parameters allowed the best classification of the 51 patients either into the WD-DEF-group or into the WD-SUS-group. CHE showed the highest significance level for a difference between the WD-DEF- and WD-SUS-group, had the highest AUC, and, in combination with ceruloplasmin, allowed 100% correct classification. Without CHE, no other combination of parameters reached this level of correct classification. After the initiation of treatment, which regularly results in an improvement in CHE, the high diagnostic accuracy of this biomarker was lost. Cholinesterase turns out to be an excellent biomarker for differentiation between untreated de novo patients with manifest WD and heterozygotic gene carriers.
HUNK Gene Alterations in Breast Cancer
Authors: Ramos-Solis Nicole , Dilday Tinslee , Kritikos Alex E. , Yeh Elizabeth S.
Published: November 2022

Hormonally upregulated neu-associated kinase (HUNK) is a serine/threonine (S/T) protein kinase related to the adenosine monophosphate-activated protein kinase (AMPK) family of kinases. HUNK was originally discovered using a screen to identify kinases expressed in the mouse mammary gland. Therefore, the majority of studies to date have been carried out in models specific to this tissue, and the kinase was named to reflect its mammary gland-specific physiology and pathology. Prior studies show a clear pathogenic role for HUNK in breast cancer. HUNK is upregulated in response to oncogenic HER2/neu and Akt, and there is strong evidence that HUNK is critical for the survival of breast cancer cells. Further evidence shows that inhibiting HUNK using a variety of breast cancer models, including those that are resistant, inhibits tumorigenesis and metastasis. However, HUNK alterations are infrequent. Here, the incidence and consequence of HUNK alterations in breast cancer is reviewed using data mined from the online database cBioPortal and considered in relation to prior research studies.
The Functional Properties and Physiological Roles of Signal-Transducing Adaptor Protein-2 in the Pathogenesis of Inflammatory and Immune Disorders
Authors: Kashiwakura Jun-ichi , Oritani Kenji , Matsuda Tadashi
Published: November 2022

Adaptor molecules play a crucial role in signal transduction in immune cells. Several adaptor molecules, such as the linker for the activation of T cells (LAT) and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76), are essential for T cell development and activation following T cell receptor (TCR) aggregation, suggesting that adaptor molecules are good therapeutic targets for T cell-mediated immune disorders, such as autoimmune diseases and allergies. Signal-transducing adaptor protein (STAP)-2 is a member of the STAP family of adaptor proteins. STAP-2 functions as a scaffold for various intracellular proteins, including BRK, signal transducer, and activator of transcription (STAT)3, STAT5, and myeloid differentiation primary response protein (MyD88). In T cells, STAP-2 is involved in stromal cell-derived factor (SDF)-1α-induced migration, integrin-dependent cell adhesion, and Fas-mediated apoptosis. We previously reported the critical function of STAP-2 in TCR-mediated T cell activation and T cell-mediated autoimmune diseases. Here, we review how STAP-2 affects the pathogenesis of T cell-mediated inflammation and immune diseases in order to develop novel STAP-2-targeting therapeutic strategies.
Plasmonic Biosensors Based on Deformed Graphene
Authors: Faramarzi Vahid , Heidari Mohsen , Zulkarnine Nik Humaidi bin Nik , Hwang Michael Taeyoung
Published: November 2022

Rapid, accurate, and label-free detection of biomolecules and chemical substances remains a challenge in healthcare. Optical biosensors have been considered as biomedical diagnostic tools required in numerous areas including the detection of viruses, food monitoring, diagnosing pollutants in the environment, global personalized medicine, and molecular diagnostics. In particular, the broadly emerging and promising technique of surface plasmon resonance has established to provide real-time and label-free detection when used in biosensing applications in a highly sensitive, specific, and cost-effective manner with small footprint platform. In this study we propose a novel plasmonic biosensor based on biaxially crumpled graphene structures, wherein plasmon resonances in graphene are utilized to detect variations in the refractive index of the sample medium. Shifts in the resonance wavelength of the plasmon modes for a given change in the RI of the surrounding analyte are calculated by investigating the optical response of crumpled graphene structures on different substrates using theoretical computations based on the finite element method combined with the semiclassical Drude model. The results reveal a high sensitivity of 4990 nm/RIU, corresponding to a large figure-of-merit of 20 for biaxially crumpled graphene structures on polystyrene substrates. We demonstrate that biaxially crumpled graphene exhibits superior sensing performance compared with a uniaxial structure. According to the results, crumpled graphene structures on a titanium oxide substrate can improve the sensor sensitivity by avoiding the damping effects of polydimethylsiloxane substrates. The enhanced sensitivity and broadband mechanical tunability of the biaxially crumpled graphene render it a promising platform for biosensing applications.
Application of the Coupled Markov Chain in Soil Liquefaction Potential Evaluation
Authors: Wen Hsiu-Chen , Li An-Jui , Lu Chih-Wei , Chen Chee-Nan
Published: November 2022

The evaluation of localized soil-liquefaction potential is based primarily on the individual evaluation of the liquefaction potential in each borehole, followed by calculating the liquefaction-potential index between boreholes through Kriging interpolation, and then plotting the liquefaction-potential map. However, misjudgments in design, construction, and operation may occur due to the complexity and uncertainty of actual geologic structures. In this study, the coupled Markov chain (CMC) method was used to create and analyze stratigraphic profiles and to grid the stratum between each borehole so that the stratum consisted of several virtual boreholes. The soil-layer parameters were established using homogenous and random field models, and the subsequent liquefaction-potential-evaluation results were compared with those derived using the Kriging method. The findings revealed that within the drilling data range in this study, the accuracy of the CMC model in generating stratigraphic profiles was greater than that of the Kriging method. Additionally, if the CMC method incorporated with random field parameters were to be used in engineering practice, we recommend that after calculating the curve of the mean, the COV should be set to 0.25 as a conservative estimation of the liquefaction-potential interval that considers the evaluation results of the Kriging method.
Examining Built Environment Professionals′ Willingness to Pay for Green Buildings in Ghana
Authors: Kumah Victoria Maame Afriyie , Agyekum Kofi , Botchway Edward Ayebeng , Pittri Hayford , Danso Frederick Owusu
Published: November 2022

The participation of built environment (BE) professionals is essential in pushing the agenda of green buildings (GBs) in the construction industry. Considering willingness to pay (WTP) in light of these professionals plays a role in the management of the construction industry as one of the major energy consumers and emitters of greenhouse gases. This study, from an extended perspective of green building, seeks to examine the factors that influence Built Environment (BE) Professionals’ willingness to pay for green buildings in Ghana. A questionnaire survey was used to solicit the views of the professionals on the theme under investigation. Purposive and snowball sampling techniques were used to obtain 153 responses from BE professionals such as architects, quantity surveyors, construction managers, and project managers in Kumasi and Accra. Both descriptive (mean, standard deviation, and standard error) and inferential statistics (one-sample t-test) were used to analyze the data. The study revealed that perceived benefit stood out as the topmost factor that BE professionals consider in their willingness to pay for green buildings. This paper could serve as an eye-opener to aid in the development of strategies and influencing mechanisms to stimulate the interest of various groups of BE professionals in delivering a more environmentally friendly construction system. This study contributes to the state-of-the-art studies regarding willingness to pay for GBs. The global literature is largely focused on the willingness of household consumers/clients to pay for GBs to the detriment of the BE professionals, who play key role in GB developments, and encourage their adoption. The novelty of this study stems from the fact that it is the first time the views of BE professionals are examined when it comes to their willingness to pay for green buildings.
Living Together for a Better Life: The Impact of Cooperative Housing on Health and Quality of Life
Authors: Reyes Alexia , Novoa Ana M. , Borrell Carme , Carrere Juli , Pérez Katherine , Gamboa Cristina , Daví Lali , Fernández Ana
Published: November 2022

To guarantee the right to adequate housing is crucial worldwide, and even more so in Spain, where there is an accumulated delay in public housing policies compared to other European countries. This situation has led to an increase in Catalonia of cooperative housing under a grant-of-use (GoU) model based on collective ownership, and the intention of people to live together, sharing daily life, and collectivizing risks and care-based work. These characteristics may impact on people’s health, but evidence is yet limited. Our study aims to explore the mechanisms that explain the relationship between cooperative housing under a GoU model and health in Catalonia. A descriptive−exploratory qualitative study was carried out. A total of 26 participants from 11 housing cooperatives were interviewed. Our results indicate that the impact of cooperative housing on people’s health is mainly explained by these components: (1) living aligned with their political motivations; (2) legal and economic aspects; (3) communal living; (4) governance, decision-making and participation; and (5) material aspects of the dwelling. Despite having health benefits, the lack of clarity in the Spanish legal framework and public funding makes universal access difficult, but it is a step forward in breaking with the speculative housing dynamics that exist in our context.
MRI- and Histologic-Molecular-Based Radio-Genomics Nomogram for Preoperative Assessment of Risk Classes in Endometrial Cancer
Authors: Celli Veronica , Guerreri Michele , Pernazza Angelina , Cuccu Ilaria , Palaia Innocenza , Tomao Federica , Di Donato Violante , Pricolo Paola , Ercolani Giada , Ciulla Sandra , Colombo Nicoletta , Leopizzi Martina , Di Maio Valeria , Faiella Eliodoro , Santucci Domiziana , Soda Paolo , Cordelli Ermanno , Perniola Giorgia , Gui Benedetta , Rizzo Stefania , Della Rocca Carlo , Petralia Giuseppe , Catalano Carlo , Manganaro Lucia
Published: November 2022

High- and low-risk endometrial carcinoma (EC) differ in whether or not a lymphadenectomy is performed. We aimed to develop MRI-based radio-genomic models able to preoperatively assess lymph-vascular space invasion (LVSI) and discriminate between low- and high-risk EC according to the ESMO-ESGO-ESTRO 2020 guidelines, which include molecular risk classification proposed by “ProMisE”. This is a retrospective, multicentric study that included 64 women with EC who underwent 3T-MRI before a hysterectomy. Radiomics features were extracted from T2WI images and apparent diffusion coefficient maps (ADC) after manual segmentation of the gross tumor volume. We constructed a multiple logistic regression approach from the most relevant radiomic features to distinguish between low- and high-risk classes under the ESMO-ESGO-ESTRO 2020 guidelines. A similar approach was taken to assess LVSI. Model diagnostic performance was assessed via ROC curves, accuracy, sensitivity and specificity on training and test sets. The LVSI predictive model used a single feature from ADC as a predictor; the risk class model used two features as predictors from both ADC and T2WI. The low-risk predictive model showed an AUC of 0.74 with an accuracy, sensitivity, and specificity of 0.74, 0.76, 0.94; the LVSI model showed an AUC of 0.59 with an accuracy, sensitivity, and specificity of 0.60, 0.50, 0.61. MRI-based radio-genomic models are useful for preoperative EC risk stratification and may facilitate therapeutic management.
Psychosocial Care after Cancer Diagnosis: Recent Advances and Challenges
Authors: Tack Laura , Schofield Patricia , Boterberg Tom , Chandler Rebecca , Parris Christopher N. , Debruyne Philip R.
Published: November 2022

Psychosocial oncology is coming of age [...]
The Effect of Melatonin Intake on Survival of Patients with Breast Cancer—A Population-Based Registry Study
Authors: Pistiolis Leda , Khaki Djino , Kovács Anikó , Olofsson Bagge Roger
Published: November 2022

Previous research has demonstrated the antitumoral effects of melatonin on breast cancer in both in vitro and in vivo studies. The aim of the present study was to investigate whether melatonin has a favorable effect on the survival of patients diagnosed with early breast cancer. This retrospective registry-based study included all patients diagnosed with breast cancer in Sweden between 2005 and 2015. Data were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Registry. A multivariate Cox regression model, including patient age, tumor size, tumor grade, ER status, HER2 status, nodal status and defined daily doses (DDDs) of melatonin, was used to analyze breast-cancer-specific survival as well as overall survival. Of the 37,075 included patients, 926 (2.5%) were prescribed melatonin, with a median DDD of 30. Melatonin was found to have a protective effect on breast-cancer-specific survival (BCSS) in the univariate analysis (HR: 0.736, 95% CI: 0.548–0.989, p = 0.042), but when adjusting for known prognostic factors in the multivariate analysis, this beneficial effect disappeared (HR: 1.037, 95% CI: 0.648–1.659, p = 0.879). Melatonin was not proven to have a favorable effect on the survival of patients diagnosed with early breast cancer in this retrospective registry study.
Sex Biases in Cancer and Autoimmune Disease Incidence Are Strongly Positively Correlated with Mitochondrial Gene Expression across Human Tissues
Authors: Crawford David R. , Sinha Sanju , Nair Nishanth Ulhas , Ryan Bríd M. , Barnholtz-Sloan Jill S. , Mount Stephen M. , Erez Ayelet , Aldape Kenneth , Castle Philip E. , Rajagopal Padma S. , Day Chi-Ping , Schäffer Alejandro A. , Ruppin Eytan
Published: November 2022

Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 167 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that, indeed, the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. The common key factor whose levels across human tissues are most strongly associated with these incidence rate sex biases is the sex bias in the expression of the 37 genes encoded in the mitochondrial genome.
Diagnostics Using Non-Invasive Technologies in Dermatological Oncology
Authors: Soglia Simone , Pérez-Anker Javiera , Lobos Guede Nelson , Giavedoni Priscila , Puig Susana , Malvehy Josep
Published: November 2022

The growing incidence of skin cancer, with its associated mortality and morbidity, has in recent years led to the developing of new non-invasive technologies, which allow an earlier and more accurate diagnosis. Some of these, such as digital photography, 2D and 3D total-body photography and dermoscopy are now widely used and others, such as reflectance confocal microscopy and optical coherence tomography, are limited to a few academic and referral skin cancer centers because of their cost or the long training period required. Health care professionals involved in the treatment of patients with skin cancer need to know the implications and benefits of new non-invasive technologies for dermatological oncology. In this article we review the characteristics and usability of the main diagnostic imaging methods available today.
Clinical Management of Supratentorial Non-Skull Base Meningiomas
Authors: Adekanmbi Adefisayo , Youngblood Mark W. , Karras Constantine L. , Oyetunji Ephraim A. , Kalapurakal John , Horbinski Craig M. , Najem Hinda , Hill Virginia B. , Chandler James P. , Heimberger Amy B. , Magill Stephen T. , Lukas Rimas V.
Published: November 2022

Supratentorial non-skull base meningiomas are the most common primary central nervous system tumor subtype. An understanding of their pathophysiology, imaging characteristics, and clinical management options will prove of substantial value to the multi-disciplinary team which may be involved in their care. Extensive review of the broad literature on the topic is conducted. Narrowing the scope to meningiomas located in the supratentorial non-skull base anatomic location highlights nuances specific to this tumor subtype. Advances in our understanding of the natural history of the disease and how findings from both molecular pathology and neuroimaging have impacted our understanding are discussed. Clinical management and the rationale underlying specific approaches including observation, surgery, radiation, and investigational systemic therapies is covered in detail. Future directions for probable advances in the near and intermediate term are reviewed.
Patient-Reported Outcomes in Cancer Patients with HIV
Authors: Coghill Anna E. , Brownstein Naomi C. , Sinha Sweta , Thompson Zachary J. , Dickey Brittney L. , Hoogland Aasha I. , Johnstone Peter A. , Suneja Gita , Jim Heather S.
Published: November 2022

Elevated cancer-specific mortality in PWH has been demonstrated for non-AIDS-defining malignancies. However, additional clinical endpoints of interest, including patient-reported outcomes (PROs), have not been systematically examined in PWH and cancer. We evaluated differences in patient-reported symptomology between cancer patients with versus without HIV using data from 12,529 patients at the Moffitt Cancer Center, including 55 with HIV. The symptoms were assessed using the Edmonton Symptom Assessment Scale (ESAS), which asks patients to rank 12 symptoms on a scale of 1–10, with scores ≥7 considered severe. The responses across all questions were summed to create a composite score. Vital status through t July 2021 was determined through linkage to the electronic health record. PWH reported a higher composite ESAS score on average (44.4) compared to HIV-uninfected cancer patients (30.7, p-value < 0.01). In zero-inflated negative binomial regression models adjusted for cancer site, sex, and race, the composite ESAS scores and the count of severe symptoms were 1.41 times (95% CI: 1.13–1.77) and 1.45 times (95% CI: 1.09–1.93) higher, respectively, in cancer patients with HIV. Among PWH, higher ESAS scores were associated with mortality (p-value = 0.02). This is the first demonstration of uniquely poor PROs in PWH and cancer and suggests that patient symptom monitoring to improve clinical endpoints deserves further study.
ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers
Authors: Yang Yufei , Zhu Ting , Wang Xu , Xiong Fen , Hu Zhangmin , Qiao Xuehan , Yuan Xiao , Wang Deqiang
Published: November 2022

The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer.
Acetyl-CoA Counteracts the Inhibitory Effect of Antiandrogens on Androgen Receptor Signaling in Prostate Cancer Cells
Authors: Makhov Peter , Fazliyeva Rushaniya , Tufano Antonio , Uzzo Robert G. , Cai Kathy Q. , Serebriiskii Ilya , Snyder Nathaniel W. , Andrews Andrew J. , Kolenko Vladimir M.
Published: November 2022

The commonly used therapeutic management of PC involves androgen deprivation therapy (ADT) followed by treatment with AR signaling inhibitors (ARSI). However, nearly all patients develop drug-resistant disease, with a median progression-free survival of less than 2 years in chemotherapy-naïve men. Acetyl-coenzyme A (acetyl-CoA) is a central metabolic signaling molecule with key roles in biosynthetic processes and cancer signaling. In signaling, acetyl-CoA serves as the acetyl donor for acetylation, a critical post-translational modification. Acetylation affects the androgen receptor (AR) both directly and indirectly increasing expression of AR dependent genes. Our studies reveal that PC cells respond to the treatment with ARSI by increasing expression of ATP-citrate lyase (ACLY), a major enzyme responsible for cytosolic acetyl-CoA synthesis, and up-regulation of acetyl-CoA intracellular levels. Inhibition of ACLY results in a significant suppression of ligand-dependent and -independent routes of AR activation. Accordingly, the addition of exogenous acetyl-CoA, or its precursor acetate, augments AR transcriptional activity and diminishes the anti-AR activity of ARSI. Taken together, our findings suggest that PC cells respond to antiandrogens by increasing activity of the acetyl-coA pathway in order to reinstate AR signaling.
Advanced Adrenocortical Carcinoma: From Symptoms Control to Palliative Care
Authors: Ruggiero Elena , Tizianel Irene , Caccese Mario , Lombardi Giuseppe , Pambuku Ardi , Zagonel Vittorina , Scaroni Carla , Formaglio Fabio , Ceccato Filippo
Published: November 2022

The prognosis of patients with advanced adrenocortical carcinoma (ACC) is often poor: in the case of metastatic disease, five-year survival is reduced. Advanced disease is not a non-curable disease and, in referral centers, the multidisciplinary approach is the standard of care: if a shared decision regarding several treatments is available, including the correct timing for the performance of each one, overall survival is increased. However, many patients with advanced ACC experience severe psychological and physical symptoms secondary to the disease and the cancer treatments. These symptoms, combined with existential issues, debase the quality of the remaining life. Recent strong evidence from cancer research supports the early integration of palliative care principles and skills into the advanced cancer patient’s trajectory, even when asymptomatic. A patient with ACC risks quickly suffering from symptoms/effects alongside the disease; therefore, early palliative care, in some cases concurrent with oncological treatment (simultaneous care), is suggested. The aims of this paper are to review current, advanced ACC approaches, highlight appropriate forms of ACC symptom management and suggest when and how palliative care can be incorporated into the ACC standard of care.
ATR Inhibitors in Platinum-Resistant Ovarian Cancer
Authors: Li Siyu , Wang Tao , Fei Xichang , Zhang Mingjun
Published: November 2022

Platinum-resistant ovarian cancer (PROC) is one of the deadliest types of epithelial ovarian cancer, and it is associated with a poor prognosis as the median overall survival (OS) is less than 12 months. Targeted therapy is a popular emerging treatment method. Several targeted therapies, including those using bevacizumab and poly (ADP-ribose) polymerase inhibitor (PARPi), have been used to treat PROC. Ataxia telangiectasia and RAD3-Related Protein Kinase inhibitors (ATRi) have attracted attention as a promising class of targeted drugs that can regulate the cell cycle and influence homologous recombination (HR) repair. In recent years, many preclinical and clinical studies have demonstrated the efficacy of ATRis in PROC. This review focuses on the anticancer mechanism of ATRis and the progress of research on ATRis for PROC.
Use of Selective Serotonin Reuptake Inhibitors Is Associated with a Lower Risk of Colorectal Cancer among People with Family History
Authors: Zhang Naiqi , Sundquist Jan , Sundquist Kristina , Ji Jianguang
Published: November 2022

Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical and population-based evidence suggests that selective serotonin reuptake inhibitors (SSRIs) might play a role in preventing CRC. We performed a nationwide cohort study to explore whether the use of SSRIs could reduce CRC risk among individuals with family history. We identified individuals aged 50 and above who had one or more first-degree relatives diagnosed with CRC. A total of 38,617 incident SSRI users were identified and matched with 115,851 non-users, on a ratio of 1:3. The Cox regression model was used to calculate hazard ratios (HRs) and 95% CI confidence intervals (CIs). We found a significant negative association between SSRI use and the risk of CRC (adjusted HR, 0.77; 95% CI, 0.70–0.85). Restricted cubic spline regression showed a non-linear dose-responded relationship between SSRI use and CRC risk. The association was stronger in rectal cancer than colon cancer (adjusted HR, 0.73 vs. 0.79), and more pronounced in advanced-stage CRC than early-stage CRC (adjusted HR, 0.73 vs. 0.80). This population-based cohort study suggests that the use of SSRIs is associated with a reduced risk of CRC among individuals with a family history of CRC.
Targeting Menin and CD47 to Address Unmet Needs in Acute Myeloid Leukemia
Authors: Matthews Andrew H. , Pratz Keith W. , Carroll Martin P.
Published: November 2022

After forty years of essentially unchanged treatment in acute myeloid leukemia (AML), innovation over the past five years has been rapid, with nine drug approvals from 2016 to 2021. Increased understanding of the molecular changes and genetic ontology of disease have led to targeting mutations in isocitrate dehydrogenase, FMS-like tyrosine kinase 3 (FLT3), B-cell lymphoma 2 and hedgehog pathways. Yet outcomes remain variable; especially in defined molecular and genetic subgroups such as NPM1 (Nucleophosmin 1) mutations, 11q23/KMT2A rearranged and TP53 mutations. Emerging therapies seek to address these unmet needs, and all three of these subgroups have promising new therapeutic approaches. Here, we will discuss the normal biological roles of menin in acute leukemia, notably in KMT2A translocations and NPM1 mutation, as well as current drug development. We will also explore how CD47 inhibition may move immunotherapy into front-line settings and unlock new treatment strategies in TP53 mutated disease. We will then consider how these new therapeutic advances may change the management of AML overall.
Assessing Spatial Distribution of Multicellular Self-Assembly Enables the Prediction of Phenotypic Heterogeneity in Glioblastoma
Authors: Cha Junghwa , Sim Woogwang , Yong Insung , Park Junseong , Shim Jin-Kyoung , Chang Jong Hee , Kang Seok-Gu , Kim Pilnam
Published: November 2022

Phenotypic heterogeneity of glioblastomas is a leading determinant of therapeutic resistance and treatment failure. However, functional assessment of the heterogeneity of glioblastomas is lacking. We developed a self-assembly-based assessment system that predicts inter/intracellular heterogeneity and phenotype associations, such as cell proliferation, invasiveness, drug responses, and gene expression profiles. Under physical constraints for cellular interactions, mixed populations of glioblastoma cells are sorted to form a segregated architecture, depending on their preference for binding to cells of the same phenotype. Cells distributed at the periphery exhibit a reduced temozolomide (TMZ) response and are associated with poor patient survival, whereas cells in the core of the aggregates exhibit a significant response to TMZ. Our results suggest that the multicellular self-assembly pattern is indicative of the intertumoral and intra-patient heterogeneity of glioblastomas, and is predictive of the therapeutic response.
BG34-200 Immunotherapy of Advanced Melanoma
Authors: Roche Veronique , Sandoval Victor , Senders Zachary , Lyons Joshua , Wolford Claire , Zhang Mei
Published: November 2022

High levels of myeloid-derived cells are characteristic of the tumor microenvironment (TME) of advanced melanoma. These cells interact with tumor cells to suppress the development of antitumor immune responses, regulate tumor metastasis, and drive cancer’s resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes, where they triggered the generation of tumor-antigen-specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T cells to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor-cell challenge. The scientific findings from this study will allow us to develop new technology and apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy.
Site-Coded Oral Squamous Cell Carcinoma Evaluation by Optical Coherence Tomography (OCT): A Descriptive Pilot Study
Authors: Panzarella Vera , Buttacavoli Fortunato , Gambino Alessio , Capocasale Giorgia , Di Fede Olga , Mauceri Rodolfo , Rodolico Vito , Campisi Giuseppina
Published: November 2022

Optical Coherence Tomography (OCT) is an emerging non-invasive method for oral diagnostics, proving to be a practicable device for epithelial and subepithelial evaluation. The potential validity of OCT in oral cancer assessment has been explored but, to date, there are very few investigations conducted with a systematic comparison between clinical/histological and OCT parameters, especially in strict reference to the anatomical site-codification of the oral mucosa. In this regard, our study performed a two-steps evaluation (in vivo OCT and histological investigations) of suspected OSCCs, progressively recruited, using as references the OCT images of the same site-coded healthy mucosa, to provide as much as possible site-specific determinants. Thirty histologically confirmed OSCCs were recruited. Specific OCT mucosal features (SEL—Stratified Epithelial Layer; BM—Basement Membrane; LP—Lamina Propria) were registered and processed using the SRQR (Standards for Reporting Qualitative Research) statement. The systematic dual descriptive OCT analysis revealed that OSCC scans present a complete alteration of epithelial (KL, SEL) and subepithelial (BM, LP) layers with a site-specificity characteristic; moreover, peculiar OCT configurations such as “icicle-like” structures could be strongly suggestive of neoplastic infiltration. This study supports the OCT use for the development of more specific optical structural models applied to oral carcinogenesis.
Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53–Mutated Metastatic Colorectal Cancer
Authors: Lahoz Sara , Rodríguez Adela , Fernández Laia , Gorría Teresa , Moreno Reinaldo , Esposito Francis , Oliveres Helena , Albiol Santiago , Saurí Tamara , Pesantez David , Riu Gisela , Cuatrecasas Miriam , Jares Pedro , Pedrosa Leire , Pineda Estela , Postigo Antonio , Castells Antoni , Prat Aleix , Maurel Joan , Camps Jordi
Published: November 2022

Next–generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first–line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time–dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double–mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK–IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time–dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53–defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53–altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first–line regimens.
Clinical Application of Poly(ADP-ribose) Polymerase (PARP) Inhibitors in Prostate Cancer
Authors: Inderjeeth Andrisha-Jade , Topp Monique , Sanij Elaine , Castro Elena , Sandhu Shahneen
Published: November 2022

Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.
Hubbing the Cancer Cell
Authors: Zhou Jingkai , Corvaisier Matthieu , Malycheva Darina , Alvarado-Kristensson Maria
Published: November 2022

Oncogenic transformation drives adaptive changes in a growing tumor that affect the cellular organization of cancerous cells, resulting in the loss of specialized cellular functions in the polarized compartmentalization of cells. The resulting altered metabolic and morphological patterns are used clinically as diagnostic markers. This review recapitulates the known functions of actin, microtubules and the γ-tubulin meshwork in orchestrating cell metabolism and functional cellular asymmetry.
Specifics of Young Gastric Cancer Patients: A Population-Based Analysis of 46,110 Patients with Gastric Cancer from the German Clinical Cancer Registry Group
Authors: Kist Markus , Thomaschewski Michael , Keck Yannick , Abdalla Thaer S. A. , Zeissig Sylke Ruth , Kleihues-van Tol Kees , Wellner Ulrich Friedrich , Keck Tobias , Hoeppner Jens , Hummel Richard
Published: November 2022

Introduction: 2–8% of all gastric cancer occurs at a younger age, also known as early-onset gastric cancer (EOGC). The aim of the present work was to use clinical registry data to classify and characterize the young cohort of patients with gastric cancer more precisely. Methods: German Cancer Registry Group of the Society of German Tumor Centers—Network for Care, Quality and Research in Oncology (ADT)was queried for patients with gastric cancer from 2000–2016. An approach that stratified relative distributions of histological subtypes of gastric adenocarcinoma according to age percentiles was used to define and characterize EOGC. Demographics, tumor characteristics, treatment and survival were analyzed. Results: A total of 46,110 patients were included. Comparison of different groups of age with incidences of histological subtypes showed that incidence of signet ring cell carcinoma (SRCC) increased with decreasing age and exceeded pooled incidences of diffuse and intestinal type tumors in the youngest 20% of patients. We selected this group with median age of 53 as EOGC. The proportion of female patients was lower in EOGC than that of elderly patients (43% versus 45%; p < 0.001). EOGC presented more advanced and undifferentiated tumors with G3/4 stages in 77% versus 62%, T3/4 stages in 51% versus 48%, nodal positive tumors in 57% versus 53% and metastasis in 35% versus 30% (p < 0.001) and received less curative treatment (42% versus 52%; p < 0.001). Survival of EOGC was significantly better (five-years survival: 44% versus 31% (p < 0.0001), with age as independent predictor of better survival (HR 0.61; p < 0.0001). Conclusion: With this population-based registry study we were able to objectively define a cohort of patients referred to as EOGC. Despite more aggressive/advanced tumors and less curative treatment, survival was significantly better compared to elderly patients, and age was identified as an independent predictor for better survival.