bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrinsic Reactivation of Human Endogenous Retroviruses in the Osteosarcoma
Authors: Koks Sulev , Koks Gea , Ho Xuan Dung , Maasalu Katre , Märtson Aare 
Published: November 2023

The human genome contains human endogenous retroviruses (HERVs) and they occupy around 8% of our genome. These viruses are derived from ancient infections of retroviruses that were reverse transcribed and integrated into the genome of ancestral host animals. These viral genomes were fixed and inherited for tens of millions of years ago. Almost all of the HERVs have lost their infectivity and no known HERV is presently. The role of HERVs has been shown in the different inflammatory diseases and cancers. The goal of present study was to analyse the genome‐wide transcriptional activity of HERVs in osteosarcoma. We performed RNA‐seq analysis of 36 tumor‐normal paired samples, raw sequencing data were used to identify HERV sequences and counts data as expressional activity. DESeq2 package was used for statistical analysis.We found massive and activation of HERVs in the osteosarcoma sample. More precisely, 58 different repeat element were differently described between normal and tumor bone with the FDR levele below 0.05. The most significantly upregulated elements were satellite elements ALR, ALR/ALPHA, ALR2, ALR6 and ALRA SAT elements. In addition, over‐expression of the pericentromeric human satellite II (HSATII) and the ancient mariner transposon (HSMAR1) was found. The most down‐regulated elements were HERVK22I, LTR40A, LTR40B, LTR40C and MER87B. Up‐regulation of the satellite elements during cancer has been described in some previous studies. However, genome‐wide analysis of all repetitive elements in the human genome is novel approach and could give additional information about the oncogenesis.Support or Funding InformationThis study was supported by institutional research funding (IUT20‐46) from the Estonian Research Agency and by the European Union's Seventh Framework Programme (FP7/2007‐2013) under grant agreement no. 602398 (Hyporth).
Cervical Cancer and HPV: Dilemmas and Resolution via Biomarkers
Authors: Markovic Olivera , Markovic Nenad 
Published: November 2023

Recent research reports are cooling the initial enthusiasm about HPV and cervical cancer. It has been expected since the understanding the HPV is cancer growth promoting agent and only indirectly (persistent infection) cancerogenic agent. This old/new view is expanding the value of HPV immunization (prevention of invasive cancer growth) and isCreating a new emphasis on HPV disease detection in healthy and patients with invasive cervical cancers.However, this emphasis is not to HPV infection detection, but to HPV disease detection. We like to remind our audience to the fact that HPV is highly contagious but weekly virulent agent, meaning that it can be present in many cases but is causing chronic or persistent disease only in few. It perfectly fits with epidemiological data. But it fits with cytopathological data, too.HPV is found in almost all invasive cervical cancers, but few HPV positive women develop cervical cancer. However, this relation is much more statically relevant in LSIL category where HPV disease is demonstrated as koilocytosis. HPV disease is diagnosed by morphological appearance of warts and cytopathological appearance of special cells – koilocytes. It is then clear that presence of koilocytes mean worse prognosis for the patients who has HPV disease positive signs together with DNA alteration positive signs – diagnosis of LSIL.A composite biomarker, MEDYKO (FASEB 2016, v. 30, No. 1, Suppl. 696.5), contains a metabolic marker CAP which identifies abnormal cells on Pap smears that may proceed into cervical cancer. As metabolic markers appear before morphology, the presence of CAP (cervical acid phosphatase) in epithelial cells on Pap smears are signs even earlier than morphological DNA changes, and could easily be a usable alarm of pending cervical dysplasia. Thus, CAP may widen the region of morphologically suspicious Pap test slides to categories ASC‐US, BCC and RCC; hence, to reduce the inevitable false negative rates of the Pap smear morphology.In conclusion, a combination of three biomarkers, all visible under the microscope, CAP, HPV and DNA could improve the Pap testing making it more accurate – sensitivity increased by CAP; specificity by HPV; faster – only one quality smear is needed, and for lower cost – all three parameters are visible on the same smear. Additional advantage is amenability of those images for digital image analysis and for electronic transfer enabling mobile telemedicine based mass cervical cancer screening globally.Support or Funding InformationGlobal Academy for Women's Health is supporting BioSciCon, Inc. which is sponsoring development of tools for mass cervical cancer screening globally.
Heparan Sulfate Proteoglycans Mediate Renal Carcinoma Metastasis
Authors: Qazi Henry , Shi Zhong‐Dong , Song Jonathan W , Cancel Limary M , Munn Lance L , Tarbell John M 
Published: November 2023

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow‐enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression.
Heparan sulfate knockdown induced reduction in invasive tumor colonies per tissue sample for both the single clone and combined clones models*

Single Clone Model
Combined Clones Model

Control
Knockdown
Δ%
Control
Knockdown
Δ%

Kidney
1.8
0.3
−86
0.8†
0.0
−100†

Liver
1.7
0.1
−97
2.1
0.1
−94

Lungs
14.6
0.5
−97
7.2
0.1
−98

Abdomen
3.3
0.3
−92
2.6
0.0
−100

Spleen
1.8
0.0
−100
0.4†
0.0
−100†

p < 0.005 for each comparison between the number of invasive tumor colonies formed by either the control (CtGFP) or knockdown (shORG‐8) cell lines within each tissue type**
0.005 < p < 0.05 for the samples in the combined clones models where there were fewer observed cases of invasive colonies formed by the control (CtGFP) cell line
n=165 tissue samples for the single clone control case. n=66 tissue samples for the single clone knockdown case, and n=50 for the paired cases in the combined clones model
3,4,2,4 Tetrahydroxychalcone (Butein) Inhibition of TNFα‐Induced CCL2 Release in Triple Negative Breast Cancer Cells
Authors: Horton Anisley C , Bauer David F. , Soliman Karam F. 
Published: November 2023

Butein is a natural 3,4,2,4 tetrahydroxychalcone compound found in the Asian tree Rhus verniciflua, which is traditionally used for cancer treatment. Monocyte chemotactic protein‐1 (MCP‐1/CCL2) is released by tumor tissues, acting as a potent chemokine enabling the mononuclear cells to differentiate into tumor‐associated macrophages (TAMs). TAMs promote tumor progression, invasion, infiltration, and dissemination. The presence of TAMs in the tumors are associated with poor prognosis and increased mortality in breast cancers. Compounds, which can attenuate or inhibit the release of CCL2 have been shown to prevent cancer‐associated pro‐oncogenic processes. In this study; we evaluated the effects of butein on the release of TNFα ‐ induced tumor promoting chemokines in triple negative breast cancer (TNBC), MDA‐MB‐231 cells. Our studies were performed using antibody microarrays which specifically showed that TNFα (40 ng/mL) induced protein expression of CCL‐2, GM‐CSF, angiogenin, GRO‐alpha, osteoprotegerin and IL‐8, were attenuated by the administration of butein (5 μM). Moreover, the effects of butein on the attenuation of TNFα mediated CCL‐2 release were validated by ELISA (68% inhibition). These findings provide evidence to suggest that butein can modulate immunological signaling of cancer cells, which can prevent the cascades that direct TAMs infiltration, a pivotal role in tumor cell initiation, progression, invasion, and dissemination.Support or Funding InformationSupported by NIH Grants G12 MD007582 and P20 MD 006738
Hypoxia stimulates an increase of Neuropeptide Y Y1 and Y5 receptor expression in human breast cancer cells
Authors: Medeiros Philip John , Uniacke James 
Published: November 2023

A hypoxic microenvironment is a common physiological attribute in solid tumors. Low O2 in tumors promotes a malignant phenotype, associated with increased proliferative, angiogenic and metastatic potential. Accumulating evidence suggests that neuroendocrine factors and their corresponding receptors may contribute to the initiation, development and progression of various cancers. Neuropeptide Y (NPY) and its receptors have been implicated as such a factor in the progression of breast cancer. Previous studies have reported the expression of the Y1R and Y5R receptor subtypes in human breast cancer cells and tumors. We have demonstrated that in breast cancer cells, NPY stimulation of Y5R increased proliferation and migration, and induced the release of vascular endothelial growth factor. In the current study, we examined the effects of O2 concentration on NPY receptor expression in MCF‐7 and MDA‐MB‐231 cells. Using quantitative PCR (qPCR) and Western blot, we compared Y1R and Y5R mRNA and protein expression in cells exposed to 1% (hypoxia) and 21% (normoxia) O2. Y1R and Y5R mRNA was quantified after 1h, 3h, 6h, 12h and 24h of hypoxia. Relative to normoxic cells, we observed a significant increase in Y1R and Y5R mRNA after 3h's of hypoxia in both cell lines. Protein expression of Y1R and Y5R was examined after a 24h hypoxic exposure. Y1R increased 2‐fold (MDA‐MB231) compared to normoixa. Y5R expression increased 79% (MCF‐7) and 55% (MDA‐MB231) relative to normoxic cells. Previous work from our group has demonstrated that hypoxic cancer cells require eukaryotic initiation factor 4E2 (eIF4E2) to direct the cap‐dependent translation of select mRNAs, therefore we tested whether the hypoxia‐induced increases in Y1R and Y5R expression were dependent on eIF4E2. Using MDA‐MB 231 cells depleted of eIF4E2, we found that hypoxic treatment had no effect on Y1R and Y5R expression compared to normoxic cells. These data provide insight into the O2‐mediated regulation of NPY receptors in breast cancer. Taken together with our previous functional NPY receptor studies, our findings provide further evidence of pathological implications of the NPY system in breast cancer. Ongoing studies will further elucidate the transcriptional and translational regulation of NPY receptors in response to hypoxia.Support or Funding InformationSupported by Ontario Ministry of Research and Innovation and Cancer Research Society
Uncoupling Effects of ERα on LKB1/AMPK Signaling Induced by Adiponectin in Breast Cancer Cells
Authors: Mauro Loredana , Naimo Giuseppina Daniela , Gelsomino Luca , Spina Elena , Panno Maria Luisa , Andò Sebastiano 
Published: November 2023

Obesity is increasingly recognized as an oncogenic factor. Adipose tissue is an active metabolic and endocrine organ that secretes many adipocytokines, which act as key mediators in several obesity‐associated diseases. Among these adipocytokines, adiponectin has been proposed as having a key role in the pathogenesis of cardiovascular disease and type 2 diabetes along with other diseases such as obesity‐associated malignancies, including breast cancer. An inverse correlation is reported between obesity and adiponectin, for which low levels of adiponectin represent a risk factor for mammary cancer. It is emerging how the role of adiponectin on breast tumorigenesis seems to be dependent on cell phenotypes. In this concern, our in vitro and in vivo studies demonstrated that adiponectin, at relatively low concentrations, repressed growth in ERα‐negative breast cancer cells whereas increased proliferation in ERα‐positive cells. Adiponectin interacts with specific receptors (AdipoR1 and AdipoR2) and exerts its effects, including regulation of cell survival, apoptosis and metastasis, via a plethora of signaling pathways. The key molecule of adiponectin action is AMP‐activated protein kinase (AMPK), which is mainly activated by liver kinase B1 (LKB1).Here, we investigated the effect of adiponectin on LKB1/AMPK signaling in ERα‐negative (MDA‐MB‐231) and positive (MCF‐7) breast cancer cells. Our results indicate that, in MCF‐7 cells, adiponectin was unable to phosphorylate AMPK, while, in MDA‐MB‐231 cells, we observed an increased AMPK activation, as evidenced by the enhanced phosphorylative status and kinase activity. Concomitantly, we observed a significant activation of downstream effectors, such as mTOR and P70S6K only in ERα‐positive cells, resulting in the stimulatory effect of adiponectin on proliferation of MCF‐7 cells.The crucial role of ERα in modulating the opposite response to adiponectin, as above reported, rises from the evidence that when we knocked down ERα in MCF‐7 cells, by siRNA, AMPK phosphorylation was restored, resulting in the inactivation of mTOR and its substrate P70S6K.Then, we investigated the molecular mechanism through which ERα was able to interfere with AMPK activation. It was extremely intriguing to observe how upon adiponectin exposure LKB1 appeared localized in the nucleus with ERα, as revealed by co‐immunoprecipitation and ligation proximity assay. This addresses how, in such circumstance, LKB1 may be recruited in the nucleus impairing its capability to couple with AMPK in the cytosol. This may explain why adiponectin at low concentrations, as observed in obese women, plays a dichotomic effect on breast cancer growth depending on ERα expression.Support or Funding InformationA.I.R.C., Associazione Italiana Ricerca sul Cancro
Apigenin Modulation of Whole Transcriptome Patterns of TNFα ‐ Induced Changes in Triple Negative Breast Cancer Cells, MDA‐MB‐231
Authors: Bauer David , Mazzio Elizabeth , Soliman Karam F. 
Published: November 2023

Mortality associated with breast cancer is primarily attributable to metastasis, of which TNFα plays a central orchestrating role. TNFα acts on the breast tumor TNF receptors evoking the release of chemotactic proteins (e.g. MCP‐1/CCL2). These proteins directs massive inward infiltration/migration of tumor‐associated macrophages (TAMs), tumor‐associated neutrophils (TANs), myeloid‐derived suppressor cells (MDSCs), T‐regulatory cells (Tregs), T helper IL‐17‐producing cells (Th17s), metastasis‐associated macrophages (MAMs) and cancer‐associated fibroblasts (CAFs). These tumor embedded infiltrates collectively enable immune evasion, tumor growth, angiogenesis, and metastasis. In the current study, we investigated the potential of apigenin, a known anti‐inflammatory constituent of parsley, to alter the transcriptome patterns in TNFα treated triple negative breast cancer cells (MDA‐MB‐231). Whole genome expression profiling was carried out on Agilent Human 4 × 44 k arrays. The findings show TNFα mediated upregulation and apigenin downregulation of transcription patterns for the following genes: LAMC2, TMEM132A, TNFAIIP2, ICAM1, TLR2, IL32, IL4l1, CTSS, NEURL3, GBP5, IDO1, C3, EB13, ANO09, C1QTNF1‐AS1, BMPER, TNFSF15, IL 24, LINC00996, TRA2A, MAP3K5, LRG1, NEDD4l and PDA15. Pathway analysis shows the primary pathway involved in the effects of TNF were in the cytokine‐cytokine receptor interaction pathway, with sub‐categorical targets within the family of chemokines, TNF family and TGF‐Beta families. These data provide a general transcriptome pattern changes influence by TNFα, and modulated by apigenin in human breast cancer cellsSupport or Funding InformationThis research was supported by the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number G12 MD007582 and Grant Number P20 MD006738.
Gradient Irradiation Enhances Cell Killing Efficiency via Bystander Effects in MCF‐7 cells
Authors: Zuo Li , Zhou Tingyang 
Published: November 2023

In recent years, a large body of evidence has shown that irradiated cells can produce signaling factors to reduce the survival of neighboring less‐ or non‐irradiated cells, termed as bystander effects. Bystander effects may play an important role in non‐uniform irradiation through the enhancement of cell killing efficacy at the under‐dosed regions. In this study, we tested the hypothesis that a gradient dose design may achieve better tumor suppression compared to uniform‐dose distribution in breast cancer cells (MCF‐7). Cells were divided into three groups receiving 8‐2 Gy (gradient irradiation, GI), 5 Gy (uniform irradiation, UI) or 0 Gy (control), respectively, followed by viability and apoptosis assays at 2, 24, and 48h after irradiation. Data were analyzed using one‐way ANOVA in SPSS. P < 0.05 was considered statistically different. Our results show that both GI and UI caused significant reduction of cell survival and increased apoptosis at 2, 24 and 48h as compared to control (p < 0.05). Although at 2h the lower‐dose irradiated cells under GI showed higher viability and lower apoptosis than those of the cells receiving higher doses, the survival difference across the various regions of GI completely diminished at 24h and 48h. More cell death and apoptosis were observed in different areas of GI field as compared to those of the UI at 24 and 48h after irradiation (p < 0.05). This study highlights a superior therapeutic effect of GI over UI due to the bystander signaling.Support or Funding InformationAmerican Physiological Society (APS) 2016 S&R Foundation Ryuji Ueno Award
Funding success following STEM teacher mentoring drives classroom innovation
Authors: Rockhold Rob , Sullivan Donna , Bender Susan 
Published: November 2023

From 1994 through 2013, mentoring of high school science, technology, engineering and math (STEM) teachers in grant‐writing exercises by medical center faculty resulted in submission of 158 applications for funding of inquiry‐based classroom activities, of which 123 (78%) were funded and which brought over $575,000 of new funds into classrooms. The Base Pair Summer Research Institute at the University of Mississippi Medical Center, funded by the Howard Hughes Medical Institute, provided directed training in identifying funding sources, describing needs and delineating defined outcomes to 157 high school STEM teachers for periods of 1 to 6 weeks. Of these, 37 (24%) responded to a 2016 online survey, 31 of whom had submitted at least one application (mean of 3.6 grants/teacher, range 1–7). The majority (13) garnered from $500–$2,000 from funded applications, but 5 teachers each gained a total of over $10,000. Teachers (77%) receiving grants expressed “much more” or “more” job satisfaction, while 74% felt grant writing increased a perception of professionalism, and 83% indicated that the funding “greatly increased” or “increased” their ability to teach effectively. Students (93%) were reported to be “much more engaged” or “more engaged” in the classrooms using grant funds. Despite these findings, only 30% of teachers reported receiving “much more” (2) or “more” (7) recognition from their school administration for receipt of funding. Mentoring of high school teachers by medical center faculty builds professionalism and job satisfaction among teachers, bolsters student engagement, and provides critically needed monetary support for educational innovation in STEM classrooms. Increased efforts are needed to address the inconsistent recognition of such professional development by secondary school administrators.Support or Funding Information(Supported by Precollege Science Education awards from the Howard Hughes Medical Institute.)
The Effects of THC on Brain Mitochondria of Zebrafish
Authors: Awodu Olamide , King Adrienne Lester 
Published: November 2023

Tetrahydrocannabinol (THC) is a cannabis and is the primary psychoactive component of marijuana. Cannabinoids can exert various biological effects. It has been shown to have therapeutic applications in the medical field such as treating medical pathologies: pain, epilepsy, and movement disorders. However, there are additional studies showing the negative impacts of THC. In particular, cannabis might directly affect brain function with a special emphasis on mitochondrial function. Therefore, we hypothesize that THC will decrease mitochondrial function. The aim of this study was to analyze the effects of THC on brain mitochondrial function using the model organism Danio.rerio (zebrafish).MethodsZebrafish were exposed to 20 mg/ml of THC and brain mitochondria was isolated. Oxygen consumption in the presence of glutamate/malate was monitored to determine mitochondrial function, and results compared to control zebrafish. Basal mitochondrial respiration (State 3 and State 4) was measured using a Clark‐type oxygraph electrode system. The respiratory control ratio (RCR) was also calculated by taking the ratio of state 3 divided state 4.ResultsZebrafish exposed to THC had a significantly lower State 3 respiration compared to control (n=6, p <0.05). A decrease in state 3 respiration is notable because it indicates that THC decreases electron transport and subsequently the rate at which brain mitochondria may synthesize ATP. Moreover, the RCR was significantly lower in THC treated fish (n=6 p<0.05). A higher RCR indicates mitochondria that are more tightly coupled with better function (i.e., better quality of mitochondria), whereas a lower RCR indicates that mitochondria are more loosely coupled with poorer function (i.e., damaged mitochondria) in response to treatment.ConclusionThese data demonstrate that the bioenergetics of brain mitochondria are impaired and THC does appear to have an impact on mitochondrial function.