bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estradiol Augments the Production and Actions of Polymorphonuclear Cells to Promote Lymphangioleiomyomatosis (LAM) Progression
Authors: Minor Briaunna M N , Hammes Stephen R 
Published: May 2021

Abstract
Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by slowly growing, estrogen-sensitive metastatic smooth muscle cell-like adenomas that result in cystic lung changes and loss of pulmonary function. LAM tumors are caused by mutations in either TSC1 or TSC2 genes that induces defective inhibition of the mTORC1 pathway, leading to increased mTORC1 activity and augmented cell proliferation. We have previously reported that estrogen ablation in our uterine-specific Tsc2 knockout mouse, which grows tumors with characteristic LAM features and lung colonization potential, effects notable regression of tumors. Thus, estrogen is required for to maintain heightened mTORC1 activity and LAM-like tumor progression. Interestingly, the observed estrogen sensitivity in vivo is more markedly pronounced than that of our estrogen receptor-positive TSC2-null cells when stimulated with estradiol in vitro, suggesting that estradiol may act elsewhere—in mTORC1 independent manner—in vivo to promote LAM progression. Flow cytometry revealed large numbers of Ly-6Cint Ly-6Ghigh myeloid cells—polymorphonuclear cells or PMNs—in the blood and myometrial tumors of our uterine-specific Tsc2-null mice. Accordingly, we found that Tsc2-null tumors required PMNs for normal disease progression, as Gr-1 (Ly-6C/Ly-6G) depletion or inhibition of PMN recruitment reduced tumor growth. Therefore, we hypothesized that, in addition to direct effects of estrogen on tumor cells, estrogen might also stimulate tumor growth by promoting PMN production in the bone marrow and actions in the tumor microenvironment. Using bone marrow cultures, we found that estradiol is indeed a potent inducer of PMN production. This effect occurs equally in both male and female bone marrow. Employing both pharmacologic agents and bone marrow from ERα; knockout mice, we showed that ERα; is necessary for promoting a PMN fate for myeloid progenitors. Additionally, we have evidence implicating estrogen in the pro-tumorigenic function of PMNs co-cultured with TSC2-null cell lines. Overall, these data suggest that estradiol maybe facilitating crosstalk in LAM tumors, directly stimulating tumor cells while also promoting the production and actions of PMNs, which in turn promote tumor growth.
Evaluation of the Octreotide Acetate Pen Injector in a Formative Human Factors Study
Authors: Andre Anthony , Squittieri Nicholas , Patil Satyashodhan 
Published: May 2021

Abstract
Introduction: Subcutaneous injection of octreotide acetate is indicated to treat adults with acromegaly and diarrhea associated with carcinoid tumors or vasoactive intestinal peptide tumors. In this formative human factors study, we evaluated the readability and comprehension of the instructions for use (IFU) and ease of use of the octreotide pen injector. Methods: The study enrolled patients and healthcare practitioners who would be using the pen injector. The IFU contained a stepwise process with illustrations to detail injection administration and safe storage of the octreotide pen injector. Participants read the IFU and familiarized themselves with the device. Participants administered 2 unaided injections into skin-like pads. Injection success was defined as an attempt that delivered the correct dose into the pad. Each injection was evaluated by objective performance and subjective measures. Objective performance measures included assessment of steps necessary to deliver the correct medication dose and ensure user safety. Subjective measures included soliciting participant feedback on perceived success and difficulties administering a dose with the octreotide pen injector, as well as suggestions for improvements. Additional goals included evaluation of the IFU and octreotide pen injector usability aspects. Results: A total of 8 patients and 3 healthcare practitioners enrolled in the study. All (n = 11) participants successfully administered both injections, leading to an overall injection success rate of 100% across twenty-two injections. Subtask errors included participants priming the pen injector with the incorrect dose (n = 1) and not holding the injection button for 10 seconds after the injection (n = 2), but neither error resulted in dosing failure. Participant suggestions for improving the IFU included changes to the illustration of the plunger, reordering statements to clarify the priming process, and detailing how long to let the pen injector come to room temperature. Conclusion: Overall, participants felt the octreotide pen injector was easy to use and the instructions were clearly written and illustrated. Participant feedback and observations by moderators of the study led to recommendations for improvements to the clarity of the IFU.
Osteoblast-Induced Prostate Cancer Cell Migration and Invasion Is Mediated Through TGF-β1/SMAD2 Signal Pathway and Blocked by 17α-Estradiol
Authors: Shi Jian , Zhao Lian , Duncan Brittany , Su Jie , Manzo Jale , Liu He , Zhu Yuan-Shan 
Published: May 2021

Abstract
Prostate cancer (PCa) is curable if it is diagnosed and treated in localized and regional stage. However, PCa outcome is poor once it has distant metastasis. Approximately 70% to 100% of PCa deaths have bone metastasis, which may be associated with a specific bone microenvironment. In this study, we investigated the effect and molecular mechanism of osteoblast cells on stimulation of PCa cell migration and invasion and examined the effectiveness of 17α-estradiol on blocking osteoblast-induced PCa cell migration and invasion using in vitro cell analysis. PCa cells (PC3, LNCaP and DU145), osteoblast hFOB, kidney CV-1, breast tumor MCF-7 and liver cancer Huh-7 cells (ATCC) were cultured in RMPI-1640 or DMEM media supplemented with or without fetal bovine serum (FBS) at 37 oC in a 5% CO2-humidified incubator. hFOB condition media (HCM) without FBS were collected at different times of hFOB cell culture. Transwell and wound-healing experiments were used to determine PCa cell migration and invasion. Cell migration and invasion in PC3, DU-145 and LNCaP PCa cells were markedly promoted by co-culturing hFOB osteoblast cells or HCM, but not by cells or condition media originated from kidney (CV-1), liver (Huh-7) and breast (MCF-7). Compared to other non-osteoblast cell conditioned media, HCM had much higher levels of several cytokines and chemokines including tumor growth factor (TGF) β1. Both HCM and TGF-β1 produced a dose- and time-dependent induction of PCa cell migration and invasion as well as SMAD2 phosphorylation without altering cell proliferation. These HCM and TGF-β1 effects were inhibited by a specific TGFβ receptor inhibitor, LY2157299, as well as by 17α-estradiol in a dose-dependent manner. Most intriguing, 17α-estradiol significantly inhibited the HCM and TGF-β1-induced PCa cell migration and invasion at very low nanomolar concentrations, presumably mediated through estrogen receptor β. These findings suggest that TGF-β1 is a major factor in mediating hFOB cell stimulation of PCa cell migration and invasion, and 17α-estradiol is a potential agent to block PCa cell bone metastasis, probably through inhibition of TGF-β1/SMAD2 signal pathway.
Protein Signatures of Parathyroid Carcinomas Using Proteomic Analyses
Authors: Kong Sung Hye , Kim Jung Hee , Han Do-Hyun Han , Bae Jeong Mo , Hong Namki , Lee Joon-Hyop , Park So Young , Choi Yong Jun , Lee Sihoon , Rhee Yumie , Kim Sang Wan , Shin Chan Soo 
Published: May 2021

Abstract
Parathyroid carcinomas are rare endocrine tumors derived from the parathyroid glands with poor prognosis. Moreover, parathyroid carcinomas are resistant to radiation or drug therapy, and surgical resection is the only treatment option. Understanding the molecular pathogenesis of parathyroid carcinomas may pave the way for early diagnostic biomarkers and therapeutic targets. Therefore, we aimed to elucidate the protein signatures for parathyroid carcinomas through quantitative proteomic analyses. We performed liquid chromatography with tandem mass spectrometry (LC-MS/MS) technique with formalin-fixed paraffin-embedded (FFPE) samples and reached a quantitative depth of more than 5,000 proteins per sample. For the analyses, 23 parathyroid carcinoma and 15 adenoma samples were collected from five tertiary hospitals in Korea. Patients’ mean age was 52 years, and 24 (63%) were female. Patients with parathyroid carcinoma had higher parathyroid hormone (PTH) and serum calcium level than adenomas (PTH, 1077.6 ± 760.7, 181.8 ± 139.8 pg/mL; calcium 13.0 ± 2.8, 11.3 ± 1.0 mg/dL, respectively). From the proteomic expression profiling, there were 137 differentially expressed proteins with the cutoff of both p &lt;0.05 and fold change &gt; 1.5. Using the Ingenuity Pathway Analysis (IPA), top enriched canonical pathways in parathyroid carcinomas included glycoprotein-6 signaling related to the coagulation pathway, acute phase response, mTOR, and clathrin-/caveolar-mediated endocytosis signaling. In transcription factor analysis, TGFβ and TP53 were activated in carcinoma, and these factors were up-regulators of CD44 antigen and Annexin A2 (ANXA2) proteins. In network analysis, α-1-acid glycoprotein 1 (ORM1), laminin subunit β-2 (LAMB2), and Serpin family (SERPIN) proteins were derived as essential proteins and correlated to the AKT complex. Also, with the support vector machine (SVM)-based classification method, we derived a set of proteins that can discriminate carcinomas from adenomas, which consists of Carbonic anhydrase 4 (CA4), α/β hydrolase domain-containing protein 14B (ABHD14B), CD44, LAMB2, phosphatidylinositol transfer protein β isoform (PITPNB), and ORM1, with the lowest error rate of 11.1%. In conclusion, from the proteomics analyses of parathyroid neoplasms, newly recognized pathways - signaling related to coagulation, acute phase response, and endocytosis - were enriched in parathyroid carcinoma in addition to the known mTOR signaling pathway. The proteins such as α-1-acid glycoprotein and laminin subunit β-2 from SVM classification and network analyses could be the distinctive signature of carcinoma and may provide insights into the therapeutic target.
A Rare Case of Resistant Pigmentation
Authors: Sheth Kaushal Vinaykumar 
Published: May 2021

Abstract
Introduction: Familial glucocorticoid deficiency (FGD) is characterised by ACTH resistance & isolated glucocorticoid deficiency, with typical biochemical findings of low serum cortisol & high plasma ACTH. Patients present with hyperpigmentation (due to stimulation of MC1R by POMC products) & hypoglycemia. Clinical presentation includes failure to thrive & susceptibility to infections.
Case Report: A 14 year old girl presented to us with generalised hyperpigmentation of the skin and oral mucosa- it started when she was 4 years of age. There was history of recurrent respiratory infections around the same time the hyperpigmentation appeared - the patient required multiple hospitalisations for the same (she was admitted 3 times in 6 months). Her random serum cortisol was measured – it came out to be 8.27nmol/L. Her serum Na+ was 140 mEq/L & K+ was 3.5 mEq/L. She was also diagnosed with subclinical hypothyroidism at that time (TSH- 7.3 mIU/L, anti TPO antibodies positive). There was no history of alacrimia or achalasia. Her 17-OHP was 2.20 nmol/L. A probable diagnosis of autoimmune polyendocrine syndrome was made & oral hydrocortisone (@ 12 mg/m2) & levothyroxine (@25 mcg) was started. The patient was compliant with the treatment, but the mother complained that her hyperpigmentation improved only by 20–30 % despite continued treatment. There was no history of salt wasting crises or hospitalisations after the initiation of treatment. Her serum ACTH values were checked 2 times (2011 & 2015) and were &gt; 2000 pg/ml on both the occasions. The hydrocortisone dose was increased to 20mg/m2 for 1 year in between, without any improvement in hyperpigmentation. Patient presented to us with persistent hyperpigmentation in 2019. She was a product of consanguineous marriage. Non-compliance was ruled out. She had attained menarche at the age of 12 years. There was history of delayed pubarche (started @ age of 13 years) & axillary hair was absent. Again, her serum ACTH was &gt; 2000 pg/ml and electrolytes and BP were normal. In view of normal electrolytes with low cortisol at the time of diagnosis & persistent hyperpigmentation even on supraphysiological doses of hydrocortisone, Familial Glucocorticoid Deficiency was considered. Genetic analysis showed mutation in Thioredoxin Reductase (TXNRD2) Gene. This gene mutation has recently been reported in FGD. (Prasad R et al, JCEM Aug 2014.) Conclusion: In cases of primary adrenal insufficiency with normal electrolytes & resistant hyperpigmentation, familial glucocorticoid deficiency should be thought of. Treatment with standard glucocorticoid therapy should be given. Serum ACTH values should not be chased. The hyperpigmentation may not resolve completely. TXNRD2 deficiency leads to impaired redox homeostasis, highlights the important redox pathway in addition to defective ACTH signaling, giving us new insights in regard to steroidogenesis.
Steroid Receptor Co-Activators Regulate Metabolic Kinases to Drive Therapy Resistant ER+ Breast Cancer
Authors: Truong Thu Ha , Benner Elizabeth A , Hagen Kyla M , Temiz Nuri A , Kerkvliet Carlos Perez , Wang Ying , Cortes-Sanchez Emilio , Yang Chieh-Hsiang , Pengo Thomas , Guillen Katrin P , Welm Bryan E , Telang Sucheta , Lange Carol A , Ostrander Julie Hanson 
Published: May 2021

Abstract
Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in ER+ mammary intraductal (MIND) xenografts. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cells that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance in ER+ breast cancer.
Stress-Induced Differential miR-4633-5p Expression in Thyroid Cancer Health Disparities
Authors: Mancao Jonathan , Lee Jin , Rood Kristiana , Davis Ryan , Perez Mia , Simental Alfred , Khan Salma 
Published: May 2021

Abstract
Filipino Americans (FA) are known to have higher rates of thyroid cancer incidence and disease recurrence compared to European Americans (EA). FA are also known to be two times more likely to die of thyroid cancer compared to EA. Epidemiological studies in California have shown that thyroid cancer is the second most common cancer among FA women. Currently, there are no studies that demonstrate the mechanism behind these discrepancies. Evidence shows a strong correlation between obesity and more aggressive forms of thyroid cancer; obesity has an increased frequency in FA populations. The exact connection between the mechanisms of obesity and cancer is poorly understood. This epigenetic phenomenon may be due to microRNAs (miRNAs), which post-transcriptionally regulate gene expression. Dysregulated miRNA profiles have been associated with various diseases including obesity and cancer. MiRNAs are linked to different types of cancer; tumor suppressor genes and oncogenes are subject to modulation by dysregulated miRNAs. No study elucidates the association of miRNAs to tumor staging or prognosis in thyroid cancer health disparities. In this study, we determined miRNA expression profiles and found significant differences in the miRNA profiles between FA and EA thyroid cancer patients. Our pilot study showed several dysregulated miRNAs, from which we chose to assay dysregulated miR-4633-5p segments that are known to be associated with thyroid cancer signaling. We used QIAGEN’s miRNA extraction kit to obtain high-quality miRNA from paraffin-embedded thyroid tissues. We performed next-generation miRNA sequencing using equal number of FA and EA samples and identified the top ten significantly up- and down-regulated miRNAs from the pool of differentially expressed miRNAs by qPCR assays. Our investigation demonstrated a 1.5-2-fold higher expression of an upregulated miR-4633-5p in FA versus EA miRNA samples (n=70) after normalized to controls. In contrast, miR-323b-3p showed no difference between FA and EA after normalized to controls. For our future work, we plan to analyze multiple up- and down-regulated miRNAs by qPCR, determine whether the miRNA signatures are consistent between samples from FA versus EA, and explore the use of these miRNA signature differentials for affordable and rapid thyroid cancer screening and prognosis.
Multifocal Multisystem Langerhans Cell Histiocytosis in an Adult Female Atypically Presenting With Multiple Abdominopelvic Abscesses
Authors: Khong Brian , Hyon Maximiliano 
Published: May 2021

Abstract
Introduction: Langerhans Cell Histiocytosis (LCH) is a condition of malignant clonal proliferation of myeloid bone marrow cells that more commonly affects children than adults. Furthermore, its presentation remains variable ranging from single organ to multisystem involvement including bone, skin, lymph, liver, spleen, lung, and central nervous system. We report an unusual case of multisystem LCH in an adult female presenting with multiple soft tissue abscesses.
Case: We report a case of a 38-year-old female with a past medical history of polysubstance abuse, type 2 diabetes, polycystic ovarian syndrome, and isolated central diabetes insipidus who had multiple hospitalizations for recurrent soft tissue abscesses treated with incision and drainage and antibiotics. Imaging studies revealed multiple osteolytic lesions involving the bilateral iliac crests, acetabulum and femur, as well as an iliopsoas abscess. Given her prior history of isolated central diabetes insipidus, the possibility of LCH as the cause was entertained. Histological evaluation performed on an inguinal soft tissue sample stained positive for CD1a and S100, and a formal diagnosis of Langerhans Cell Histiocytosis (LCH) was made. The patient was treated with chemotherapy with good results.
Conclusion: This report presents a rare and unusual case of adult onset multisystem LCH involving bone, skin, lymph, and central nervous system presenting with recurrent large abdominopelvic abscesses. These abscesses may represent a rare and unrecognized form of soft tissue involvement of LCH.
Tissue Is the Issue - A Case of Malignant Insulinoma
Authors: Arous Tania , Gianfagna Sara , Del Rivero Jaydira , Harbuz-Miller Inga 
Published: May 2021

Abstract
Introduction: Insulinomas are rare, functioning pancreatic neuroendocrine tumors, predominantly benign (90%). Most are sporadic, but they can occur as part of inherited disorders. Large size insulinomas are more likely to be malignant. 68Gallium (Ga)-DOTATATE scan is an essential tool in diagnosis and treatment of pancreatic neuroendocrine tumors. However, tissue diagnosis is the ultimate prognosis predictor and treatment guide.
Clinical Case: An 80-year-old man presented with left ankle fracture after a syncopal episode. In the past several months he reported multiple episodes of lightheadedness. He denied history of diabetes. Past medical and surgical history included prostate cancer, gastroesophageal reflux disease and bilateral orchiectomy for undescended testes. His left ankle appeared swollen, otherwise the exam was unremarkable: he was well-nourished, the abdomen was soft and nontender, there were no palpable masses. He was noted to have several episodes of hypoglycemia. Hypoglycemia work up included negative sulfonylurea screen, plasma glucose 51 mg/dl (60-99 mg/dl), insulin of 31 uIU/ml (3-25 uIU/ml), proinsulin 85.4 pmol/L (&lt;8 pmol/L), C peptide 3.4 ng/ml (1.1-4.4 ng/ml). Abdominal Computed Tomography with contrast showed a 4.7 x 3.1 cm exophytic mass in the body of pancreas, a 5.3 x 5 cm mass in the head of pancreas and multiple ill-defined hepatic lesions concerning for metastatic disease. 68Ga-DOTATATE scan revealed an avid pancreatic mass and multiple avid foci throughout the liver suspicious for metastatic disease. Octreotide and intravenous dextrose were started for the treatment of persistent hypoglycemia. He underwent Whipple procedure and resection of the metastatic liver lesions. Postoperatively hypoglycemia resolved. The pathology revealed large cell pancreatic neuroendocrine carcinoma with areas of well differentiated tumor and multiple liver metastatic neuroendocrine carcinoma, Ki-67 of 50-80% was reported in the primary tumor and metastatic lesions.
Discussion: Metastatic insulinomas carry a significant morbidity and mortality risk. Surgical resection to decrease tumor burden can reduce the risk of hypoglycemia. Histopathology is essential in treatment decision making. Surprisingly our patient’s pathology revealed poorly differentiated neuroendocrine carcinoma, changing the prognosis and treatment. Treatment with platinum-based chemotherapy and etoposide is the standard of care for aggressive neuroendocrine neoplasms. Despite hypoglycemia resolution following surgery and good DOTATATE uptake by the well differentiated neuroendocrine tumor portion, our patient’s prognosis remained poor in view of the high-grade carcinoma. Due to complicated hospital course, and decreased functional status patient was not a candidate for chemotherapy immediately post hospital discharge.