bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulated electro hyperthermia inhibits tumor progression in a triple negative mouse breast cancer model
Authors: Hamar Péter , Danics Lea , Schvarcz Csaba , Zolcsák Zita , Benyó Zoltán , Kaucsár Tamás 
Published: June 2021

IntroductionThe effective therapy of triple‐negative breast cancer (TNBC) has not yet been achieved. Modulated electro‐hyperthermia (mEHT) is a novel adjuvant antitumor therapy, based on the highly selective heating of the tumor tissue by a 13.56 MHz radiofrequency current induced electric field.AimsOur aim was to investigate the effects of repeated mEHT treatment in a triple‐negative mammary carcinoma bearing mouse model.Method4T07 cells were inoculated orthotopically in female BALB/c mice. Tumor growth was monitored in vivo by digital caliper and ultrasound (Phillips Sonos 5500). The mEHT (n=8) or sham (n=9) treatments started 7 days after inoculation and were repeated 5 times, on every other day. Mice were euthanized 1 day after the fifth treatment and the tumors were dissected, weighed and processed for histology and molecular biology techniques. The ratio of the damaged area compared to the whole tumor area (Tissue Destruction Ratio, TDR) was evaluated on H&E and cleaved caspase‐3 stained sections, while HSP70, a common damage‐associated molecular signal, Ki67, a proliferation marker and p21, a tumor suppressor protein expression were analyzed on immunohistochemical staining with the HistoQuant module of the CaseViewer Software (3DHistech).ResultsThere was a significant decrease in tumor growth (sham: 5.7x, mEHT: 2.4x relative to pre‐treatment (day 6) size, p<0.0001) and weight (sham: 288.3±58.1 mg vs mEHT: 85.3±21.3 mg, p<0.05) in the mEHT treated group, compared to the sham group. The HSP70 stained area in the non‐destructed tumor tissue was 5.2 fold higher in the mEHT treated group, compared to the sham group (p<0.05). Moreover, the Ki67 positive nucleus / mm2 count was significantly lower (sham: 2823.4±211.9 pcs/mm2 vs mEHT: 1736.7±315.3 pcs/mm2, p<0.05) and the p21 positive nucleus / mm2 count showed increasing tendency (sham: 127.0±25.3 pcs/mm2 vs mEHT: 242.2±78.2 pcs/mm2, p = 0,073) in the mEHT treated group, compared to the sham group.ConclusionOur findings suggest, that repeated mEHT could lower tumor cell proliferation by promoting cell cycle arrest in vivo. Thus, mEHT could be a possible alternative adjuvant therapeutic strategy for TNBC cancer patients. We plan next generation sequencing to elucidate the biological mechanism behind the effects of mEHT.NVKP_16‐1‐2016‐0042This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anti‐angiogenic activity of memantine, a dual α7‐nAChR/ NMDAR antagonist, in human squamous cell lung cancer
Authors: Dasgupta Piyali , Robateau Zachary R , Nolan Nicholas A , Brown Kathleen C , Chen Yi Charlie , Tirona Maria R , Egleton Richard D 
Published: June 2021

Squamous cell lung cancer (SCC‐L) bears a strong etiological association with smoking habits. Nicotine, the addictive component of cigarettes, promotes angiogenesis in lung cancer via the α7‐nicotinic acetylcholine receptor (α7‐nAChR) subunit on human lung endothelial cells. Our published data shows that nicotine upregulates the expression of α7‐nAChR in SCC‐L cell lines. Therefore, we conjectured that α7‐nAChR‐antagonists should display potent anti‐angiogenic and anti‐tumor activity in SCC‐Ls. Memantine is a dual α7‐nAChR/NMDAR antagonist, which is used in the clinic for the treatment of patients suffering from mild‐to‐moderate Alzheimer's disease. Receptor binding assays have shown that the affinity of Memantine for α7‐nAChR is greater than NMDAR. Tumor‐associated endothelial cells are biochemically and morphologically distinct from normal pulmonary endothelial cells. We observed that SCC‐L associated endothelial cells (STACE) and human microvascular endothelial cells of the lung (HMEC‐Ls) expressed robust levels of α7‐nAChR and NMDAR‐1 and NMDAR‐1. Our results indicate that memantine attenuated nicotine‐induced angiogenesis in HMEC‐L. Most interestingly, the levels of α7‐nAChR in tumor‐associated endothelial cells was greater than normal lung endothelial cells. The anti‐angiogeneic activity of memantine was mediated by the α7‐nAChR (and not by NMDARs) on lung endothelial cells. Furthermore, the α7‐nAChR antagonist memantine displayed potent anti‐angiogenic activity in chicken chorioallantoic membrane (CAM) model. Our studies show that α7‐nAChR antagonists may be useful anti‐tumor agents relevant for the treatment of human lung cancer.Support or Funding InformationFunding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02), Edwards Cancer Center Pilot grant, Cabell Huntington Hospital, Marshall University. This work was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV‐INBRE) grant GM103434(PI: Dr. G. Rankin). A NASA Undergraduate Fellowship was also given to NAN.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
How the calcium influx and homeostasis might be disrupted in the Purkinje cell degeneration and cerebellar dysfunction?
Authors: Aslam Naveed , Alvi Farah 
Published: June 2021

In cerebellar circuitry the Purkinje cells (PCs) are the most prominent neuronal element and are characterized by thick and highly branched dendritic tree. The signaling molecule PKCγ is critically linked to Purkinje cell function and has a strong negative impact on the dendritic growth and development of PCs. Recent evidence links enhanced PKCγ to long‐term alteration in calcium equilibrium in PCs. Observations also show that blocking the voltage gated calcium channels could partially or completely protect Purkinje cell dendrites from stunted growth thought to be associated with enhanced PKCγ activity. Additional evidence from moon walker mutant mice also link the increased calcium influx through TRPC3 channels to dampened dendritic morphology. In this study we investigate that how the calcium influx and homoeostasis is regulated in PCs? Here, we propose an integrated model of calcium equilibrium in PCs, by converging the mGluR1 induced membrane generation of DAG and calcium influx through TRPC3 channels into an integrated signaling cascade. The model proposed here link the DAG generation after membrane depolarization to PKCγ activation as well as the activation of TRPC3 through direct binding of DAG. This proposed signaling cascade suggests that DAG signaling in Purkinje cells is tightly regulated through a double‐negative feed‐back loop. The results show that DAG‐ PKCγ‐DGKγ axis forms the first negative feedback loop whereas, the DAG‐TRPC3‐PKCγ‐DGKγ axis forms the second negative feedback loop where, both PKCγ and DGKγ molecules in second negative feedback loop are contributing due to Ca+2 influx through TRPC3 channel, which in turn, stimulates the cytosol‐to‐membrane translocation of these molecules in PCs. Our results suggest that for wild‐type case the double negative feedback on DAG and subsequently on TRPC3 channel is exquisite and specific enough to maintain the calcium homeostasis in PCs, thus ensuring their viability. However, for PKCγ with enhanced activity the second double negative feedback loop is not able to tightly regulate the gating characteristics of TRPC3 channels thus disrupting the calcium homeostasis and leading to degeneration and dysfunction of PCs.Support or Funding InformationPrivate FundingThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dissecting the Contribution of Specific Hindbrain Cell Populations in the Phenotypic Characterization of a Mouse Model of Central Congenital Hypoventilation Syndrome
Authors: Alzate‐Correa Diego , Liu Jillian , Jones Mikayla , Alves Michele Joana , Silva Talita Melo , Baer Lisa , Stanford Kristin , Czeisler Catherine , Otero Jose 
Published: June 2021

Hindbrain respiratory neuron networks undergo critical developmental maturation during the late embryonic, perinatal and post‐natal periods in mammals. Thus, abnormalities in neuron network development may contribute to autonomic respiratory dysfunction. Central Congenital Hypoventilation Syndrome (CCHS) is a rare genetic disorder characterized by an inability to sense and respond to altered levels of CO2 or O2 (Chemosensation). CCHS patients present with a spectrum of central respiratory control pathophysiologies, ranging from deficiency in chemosensation, to most severe manifestations of neonatal apnea that requires life‐sustaining mechanical ventilation. Heterozygous Mutations of the transcription factor PHOX2B, classified as either poly‐alanine repeat (PARM) and non‐poly‐alanine repeat (NPARM), have been linked to the development of CCHS. In order to explore CCHS pathophysiology, a novel transgenic mouse expressing an inducible NPARM Phox2b mutation (Phox2bΔ8) was developed and characterized by Nobuta and collaborators (Nabuta et al. 2015). Following this study and aiming to reveal the contribution of specific hindbrain populations to CCHS, we have generated two additional mouse models in which of Phox2bΔ8 expression is restricted to cell populations derived from either NKX2.2+ or OLIG3+ progenitors. Expression of Phox2bΔ8 on NKX2.2+ derived cells resulted in a strong apneic phenotype on newborn pups. Detail examination of this mouse model hindbrains showed deficiencies in a spectrum of rhombomeric nuclei not developmentally derived from NKX2.2+‐expressing progenitors, indicating that the developmental neuropathologies identified result through non‐cell‐autonomous mechanisms. Additionally, we find that these pathologies result from early rhombomeric patterning defects in embryonic ventral neural progenitor zones, which showed reduced endogenous PHOX2B expression. On the other hand, preliminary results indicate that expression of Phox2bΔ8 on OLIG3+ derived cells result in a subtle deficit in chemosensation, but we have been unable to find any neuropathological change in the hindbrain. Together, our results help to dissect the contributions of different cell populations in the hindbrain and to further clarify the different manifestations and severity of chemosensation and respiratory deficits seen in human CCHS patientsSupport or Funding InformationNIH R01HL132355This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Characterizing αSyn Pre‐Formed Fibril Animal Models and Exploring Endpoints Beyond αSyn for Parkinson Disease
Authors: Gocal Wiktoria , Gentzel Renee , Marcus Jacob 
Published: June 2021

The second most common neurodegenerative disease, Parkinson disease (PD), has been characterized by conformational mutations in the synaptic protein, alpha‐synuclein (αSyn). In the disease state, the protein becomes increasingly insoluble and aggregates, forming Lewy bodies and impairing cellular function, as seen in PD. To further study this synucleinopathy in animals, a model has been established in which αSyn Lewy bodies are induced through the addition of exogenous αSyn preformed fibrils (PFFs) (Luk et al., 2009). These PFFs allow for the “seeding” of endogenous αSyn, producing the Lewy body neuropathology typical of PD. Our group used this seeding model in‐vivo, by injecting 4 uL and 8 uL doses of 2 ug/ul PFFs directly into the striatum of wild‐type rats, and histologically examining the spread of the pathology 30 days later. Pathological αSyn is correlated with phosphorylation of the protein at serine129 (pSer129), and thus all samples were stained for pSer129 using immunohistochemistry methods at the 30 day time point.Additional endpoints were also explored to better understand the biology of PD. Aside from αSyn accumulation, PD is also characterized by neurodegeneration that could be due to an inflammatory or immune response to the aggregated protein. To explore this relationship, immunohistochemistry staining was performed for glial marker Iba‐1 to visualize microglia and GFAP to visualize astrocytes. Staining was also performed for lymphocyte‐activation gene 3 (LAG3) and major histocompatibility complex II (MHCII) as markers for a potential immune response. These results will enrich understanding of additional inflammation and immune components of this rodent model of PD.Support or Funding InformationMerck Research LaboratoriesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Fat Emboli in the Rat Brain in a Model of Fat Embolism Syndrome
Authors: Colson Jordan Dane , Siddiqi Ahsan , Van Dillen Michael , Fotouhi Ariana , Al‐Husseinawi Ethar , Al‐Allaf Jwan , Wells Brandon , Monaghan Paula , Poisner Alan , Molteni Agostino 
Published: June 2021

IntroductionFat embolism (FE) resulting from intravenous triolein (T) injection in an experimental rat model has been shown to result in severe pulmonary damage, septal and arterial inflammation, and eventually fibrosis. This tissue response appears to be biphasic in nature with a peak at 48 hours. Fat droplets have previously been reported in the brains of patients suffering severe fat embolism syndrome (FES). The current study was carried out to determine if FE in our model was also associated with fat droplets in the brain at 48 hours.Materials and Methods26 Sprague‐Dawley rats (250–330g) were divided into two groups (N=13 each) receiving either 0.2 mg intravenous T or normal saline. All animals were euthanized under isoflurane anesthesia 48 hours later. Lungs and brains were isolated, snap‐frozen, and processed for cryosectioning. Sections were stained for oil red o and hematoxylin and eosin. Sections were imaged at 400x magnification and counted by two pathologists blinded to section identity. These counts were decoded by an independent observer and statistically compared utilizing a student's T‐test.ResultsThe brains of the control group exhibited fat droplets in 3 of the 12 brains considered. These droplets were small in size and primarily localized to the cerebral cortex with minimal associated parenchymal reaction. 10 of the 12 brains observed in the experimental group demonstrated fat droplets which were localized to the cerebral cortex, cortical arteries, and especially the meningeal arteries. These droplets were much larger and were associated with an appreciable vascular thickening within affected vessels. Lungs of the control group featured a small amount of small scattered fat droplets in the same 3 subjects while the lungs of the experimental group all featured large fat droplets with the expected septal and associated arterial damage pattern previously published.ConclusionsWhile fat deposition is a non‐specific finding, the difference in tissue response demonstrated in rat lungs and brains is evident. While FE appears to provoke a marked inflammatory response within the lungs even at 48 hours the brain does not appear to reciprocate this change. While the droplets noted within the experimental group are larger and more associated with a mild vessel response the parenchyma of the brain appears much less affected compared to the lungs within the same animal. As the tissue reaction within the lungs is biphasic and the observed changes within the brain differ significantly further studies are necessary to ascertain if said changes might not evolve over a longer period of time.Support or Funding InformationSupported by the Catherine T Geldmacher foundation, Saint Louis, MO.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High scores in the embedded figures test correlate with tissue diagnostic speeded
Authors: ACERO EDWARD JAVIER 
Published: June 2021

INTRODUCTIONIn educational scenarios of tissue diagnostics, cognitive skills with high GEFT scores are valued because they are associated with more rapid diagnoses, but perceptive or confidence errors can be presented. The objective of this work was to show that students with high GEFT scores do not observe all the tissue diagnostic patterns of Fibrous Histiocytoma stained with H&E.MATERIALS AND METHODSIndividually 63 medical students were challenge to diagnostic miscroscopic with digital image of Fibrous Histiocytoma stained with H&E, and while an eye track was made, diagnostic times of begin to finish was recorded. On other site and moment, too individually a Group Embedded Figures Test (GEFT) was madeRESULTSHigh scores (Between 25 and 20 of GEFT) n= 35 students) had less time to diagnostic Fibrous Histiocytoma (X 115.1 s, SD = 13,2); and correlation (r = −0.84 P = 0.0041). and low scores less than 7 of GEFT) n= 14 students) nedded more time to diagnostic Fibrous Histiocytoma (X 132,6 s, SD = 18,5); and correlation (r = −43,1 P = 0.037). intermedium scores (Between 19 and 9 of GEFT) n= 11 students) had correlation non linear with shape "U" inverted with the more diagnostic longer times (X 157,2 s, SD = 26,8). Interesting find with eye tracking show how high scores of GEFT, not see clasical cells pattenrs of Fibrous Histiocytoma, but watch only collagen bundles; and those with intermedium and lower scores GEFT watch collagen and fibroblast bundlesDISCUSSIONAs the laws of perceptual organization state that contrast cognitive loadis used for the recognition of GEFT, in students with high scores to GEFT a faster cognitive recognition processes to diagnostic Fibrous Histyocitoma is suggested with similar mechanism, achieving by visual search only to collagen bundles stained with H&E.CONCLUSIONSHigh scores on GEFT correlate with tissue diagnostic of Fibrous Histiocytoma stained with H&E more speeded, using patterns perceptive only to collagen bundlesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RAGE Implications during DNA Double Strand Breaks in Trophoblast Cells
Authors: Tsai K YF , Hirschi K M , Knowlton M N , Mejia J F , Hall P , Davis T , Reynolds P R , Arroyo Juan A 
Published: June 2021

Intrauterine growth restriction (IUGR) is an obstetric pathology characterized by an increase in trophoblast apoptosis and decreased cell invasion. Trophoblasts are critical for a successful pregnancy and they mediate important steps such as implantation, immune protection of the fetus, maternal blood flow to the placenta, and delivery. Previous mouse studies in our laboratory showed increased trophoblast apoptosis, decreased cell invasion and increased placental receptors for advanced glycation end‐products (RAGE) during second hand smoke (SHS) treatment. More recently, a role for nuclear RAGE (nRAGE) has been implicated in DNA double strand break (DNA‐DSB) repair. We tested the hypothesis that RAGE is involved during DNA‐DSB repair in trophoblast cells. DSBs were induced in human trophoblasts (Bewo and Sw71) with cigarette smoke extract (CSE) or bleomycin (BLM). Assessment of nRAGE and g‐H2AX (involved in DNA‐DSB repair) was done by immunostaining. Invasion was measured in trophoblast cells after CSE and BLM treatment. Immunoblot was used to quantify nRAGE and g‐H2AX in cells. DNA degradation was used to determine DNA integrity.Increased Co‐expression of RAGE and y‐H2AX was observed in treated trophoblasts when compared to controls. Increases protein expression of RAGE and g‐H2AX was quantified by immunoblot in control and treated trophoblast cells . Trophoblast invasion was decreased 50% with 20ug/ml BLM treatment (p<0.0001) and 80% with 30ug/ml as compared to controls (p<0.0001). Invasion of trophoblast cells was decreased 92% (p<0.002) when treated with 0.5% CSE. Trophoblast DNA degradation was significantly detected following treatment with BLM or CSE. We conclude that CSE and BLM causes DNA‐DSBs in trophoblast cells and repair may plausibly be regulated by nRAGE and g‐H2AX. Confirmatory studies in the absence of RAGE are necessary in order to validate a possible link. DNA‐DSBs could be a factor in inhibited trophoblast invasion observed in compromised placenta. These studies provide a critical initial step in dissecting tobacco‐mediated IUGR progression.Support or Funding InformationThis work was supported by a grant from the Flight Attendant's Medical Research Institute (FAMRI, PRR and JAA) and a BYU Mentoring Environment Grant (JAA and PRR).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sex Differences in Anti‐allodynic Tolerance to Δ9‐THC in Desensitization‐resistant S426A/S430A and Wild‐type Mice
Authors: Henderson‐Redmond Angela N , Sepulveda Diana E , Hale David E , Morgan Daniel J 
Published: June 2021

Tolerance to the anti‐allodynic effects of cannabinoids has the potential to limit their therapeutic potential. A growing body of clinical and preclinical evidence suggests that sex influences a variety of cannabinoid‐related outcomes, including cannabinoid‐induced anti‐allodynia. Male and female mice expressing a desensitization‐resistant form of the cannabinoid type‐1 (CB1) receptor (S426A/S430A) show delayed tolerance to Δ9‐tetrahydrocannabinol (Δ9‐THC) in the tail‐flick assay. Likewise, using the tail‐flick test, male wild‐type mice are more sensitive than females to the anti‐nociceptive effects of Δ9‐THC across the full dose response curve. While the tail‐flick is an acute model of thermal pain, it remains unknown whether these sex‐ and/or genotype differences extend to a chronic model of neuropathic pain. The purpose of the current study was to determine whether the S426A/S430A mutation also alters tolerance to anti‐allodynic effects of Δ9‐THC in a sex‐specific manner. Male and female wild‐type and S426A/S430A mice were assessed for tolerance to the anti‐allodynic effects of 6 and 10 mg/kg of Δ9‐THC in a cisplatin‐evoked model of neuropathic pain. Female mice were less sensitive to the anti‐allodynic effects of 6 mg/kg Δ9‐THC than males. Treatment with 6 mg/kg Δ9‐THC was able to completely reverse allodynia in male, but not female, mice. Female mice showed a complete reversal of allodynia following treatment with 10 mg/kg Δ9‐THC. Interestingly, the S426A/S430A mutation did not alter sensitivity or tolerance development to the anti‐allodynic effects of Δ9‐THC compared to wild‐type mice of either sex, suggesting that the action of Δ9‐ THC at the mutant form of CB1 may be masked by its substantial anti‐allodynic effects through CB2. This study highlights the therapeutic potential of Δ9‐THC in a model of neuropathic pain and suggests that these effects might be mediated in a sex‐specific manner that may have clinical implications for the use of cannabinoids in chronic pain management.Support or Funding InformationNational Institute on Drug Abuse grant DA037355 (DJM); Penn State University College of Medicine Department of Anesthesiology & Perioperative Medicine; Pennsylvania Department of Health using CURE Tobacco Settlement Funds (DJM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.