bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microtubule-Associated Protein 2 as a DHEA Binding Protein in Endometrial Cancer
Authors: Miki Yasuhiro , Iwabuchi Erina , Takagi Kiyoshi , Suzuki Takashi , Sasano Hironobu , Ito Kiyoshi 
Published: May 2021

Abstract
Dehydroepiandrosterone (DHEA) is an androgen secreted by the adrenal glands, but its binding affinity for the androgen receptor is very low. DHEA is transformed into androstenedione by 3β-hydroxysteroid dehydrogenase (HSD) and then into testosterone by 17β-HSD type 5, or into estrone by aromatase. DHEA is also converted into androstenediol by 17β-HSD type 1. Therefore, DHEA is considered to play an important role as a precursor hormone for sex steroid hormones. We performed a search for a protein having an amino acid sequence homology to the DHEA binding site of 17β-HSD type 1, and found that microtubule-associated protein 2 (MAP2) binds to DHEA (Laurine E et al., J Biol Chem. 2003). MAP2 expression is necessary for neurite extension and cessation of cell division. MAP2 is known to suppress migration and invasion and affect the assembly, stabilization, and bundling of microtubules in melanoma cells, but the function of MAP2 in endometrial cancer has not been clarified. In this study, we investigated the expression of MAP2 and its association with DHEA in order to clarify the direct non-receptor action of DHEA in endometrial cancer. We employed frozen and formalin-fixed paraffin-embedded (FFPE) tissues of 35 endometrial cancer tissues (G1, n=12; G2, n=10; G3, n=9; Serous, n=4). Hormone concentrations were measured by liquid chromatograph-tandem mass spectrometer from the frozen sample, and immunohistochemistry of MAP2 was performed using FFPE tissues. We also examined MAP2 immunoreactivity using 59 normal endometrial tissues (proliferative phase, n=33; secretory phase, n=26) of FFPE tissue microarray slides. MAP2 immunoreactivity was found in the cytoplasm of endometrial cancer cells, and the MAP2-positive rate was significantly higher in type 1 (G1 and G2) than in type 2 (G2 and G3). The cell proliferation marker Ki-67 index was significantly lower in the MAP2-positive group. MAP2 was also detected in the glandular epithelial cells of the normal endometrium. The MAP2-positive rate was lower in the proliferative phase than in the secretory phase. Furthermore, the concentration of DHEA in the cancer tissue was significantly higher in the MAP2-positive group than in the MAP2-negative group. MAP2 is known to act on the stability of microtubules and is thought to be involved in the suppression of proliferation and infiltration in cancer cells. It was suggested that DHEA is involved in the stabilization of MAP2 and suppresses the progression of cancer in a hormone receptor-independent manner.
Systemic Immune Response in Murine Bilateral Pheochromocytoma Model During Immunotherapy Based on a Combination of Mannan-BAM, TLR Ligands and Anti-CD40 Antibodies (MBTA Therapy)
Authors: Uher Ondrej , Huynh Thanh-Truc , Zhu Boqun , Horn Lucas A , Medina Rogelio , Wang Herui , Palena Claudia , Chmelar Jindrich , Zhuang Zhengping , Zenka Jan , Pacak Karel 
Published: May 2021

Abstract
Immunotherapy has become an essential component of cancer treatment, however, a majority of patients with solid metastatic cancers, such as pheochromocytoma (PHEO), do not respond to this type of therapy. Recently, we developed an intratumoral (i.t.) immunotherapy based on the unique combination of TLR ligands, anti-CD40 antibodies, and mannan, which is artificially bound to tumor cells via an anchor (MBTA therapy). This therapy resulted in the complete eradication of aggressive subcutaneous PHEO in 67% of mice and demonstrated a systemic antitumor immune response and regression of non-treated lesions in the metastatic model (1). To further evaluate this systemic effect generated during MBTA therapy, we established a murine bilateral PHEO model, where MBTA therapy was i.t. injected into one tumor, and the distant (non-treated) tumor was monitored for changes in size and immune cell infiltration. The growth of both MBTA-treated and distant tumors was reduced compared to that of the control. Interestingly, survival of the MBTA-treated mice was twice as long compared to the control mice. Moreover, we have made several unique observations during the experiments which were focused on the tumor microenvironment. Flow cytometry analysis revealed the ability of MBTA therapy to significantly increase the infiltration of innate immune cells (monocytes, DCs, macrophages, NK cells) not only in MBTA-treated tumors, but also in distal tumors, despite the fact that MBTA therapy was designed to elicit only local inflammation. An analysis of the macrophage phenotype revealed a switch from protumor M2 to antitumor M1 macrophages in both tumors during the entire MBTA therapy treatment. Analysis of splenic adaptive immune cells revealed that naïve CD4+ or CD8+ T cells differentiated into central memory cells and effector memory cells. CD4+ and CD8+ T cells were elevated in MBTA-treated and distant tumors with a significantly higher frequency of CD8+ effector memory T cells. Moreover, the adoptive transfer of CD4+ and CD8+ T cells revealed that immune memory, after tumor rechallenging, was driven by CD4+ T cells. Collectively, these results illustrate the ability of MBTA therapy to activate both parts of the immune system and render a systemic antitumor response against non-treated metastases. We believe that our results could lead to the use of MBTA therapy in patients with aggressive, metastatic lesions. Reference: Caisova et al., Cancers (Basel), 2019. 11(5).
Triple Negative Breast Cancer is Dependent on the Lysosomal Cholesterol Transporter NPC1
Authors: O’Neill Kathleen 
Published: May 2021

Abstract
Background: Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer (BC) with peak rate of metastasis within the first few years post diagnosis and few targeted therapies. Normal epithelial cells and estrogen receptor alpha (ER) positive BC express the microRNA-200c (miR-200c), a potent suppressor of epithelial-to-mesenchymal transition (EMT). However, miR-200c is silenced or lost in TNBC, allowing aberrant expression of genes conferring a de-differentiated, non-epithelial phenotype that confers invasive and chemo-resistant properties. Recent literature demonstrated that EMT also promotes altered tumor cell metabolism. Hypothesis: We postulate that EMT reversal in TNBC will reveal selective advantages and identify novel therapeutic vulnerabilities. Methods: We used restoration of miR-200c as a tool to identify selective advantages conferred by EMT. In addition to driving global metabolic changes, miR-200c-repressed key cholesterol metabolism genes that support the uptake of dietary cholesterol, which is delivered via low-density-lipoproteins (LDL) and processed by the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1). Manipulation of NPC1 by genetic and pharmacological means was used to determine if and how TNBC are reliant on this pathway. Results: We determined that NPC1 is overexpressed in TNBC relative to ER+BC (Nature Metabric P&lt;0.0001). Restoration of miR-200c directly targets the NPC1 3’UTR and represses NPC1 by two-fold (p=0.01). While silencing of NPC1 in ER+ BC cells led to slowed proliferation, TNBC cell lines died within 48-72 hours. NPC1 is associated with mitochondrial dysfunction and mTOR suppression. Intracellular cholesterol homeostasis is critical for cell survival and is carefully regulated, but how these homeostatic mechanisms adapt during tumor progression is poorly understood. Conclusions: This study demonstrates that while mesenchymal-like TNBC cells do not require exogenous cholesterol from the microenvironment, this cancer type is sensitive to the loss of NPC1. Overall, this work identifies NPC1 as a novel target in TNBC and sheds light on how lysosomes and mitochondria interact to sense cholesterol and drive cell survival.
Using Multimodal Functional Imaging in the Management of SDHx-Related Pheochromocytoma and Paraganglioma
Authors: White Gemma , Anandappa Samantha , Masucci Michael , Hassan Fahim-Ul , Breen Louise , Joshi Mamta , McGowan Barbara , Hubbard Jonathan , Obholzer Rupert , Touska Philip , Izatt Louise , Velusamy Anand , Carroll Paul 
Published: May 2021

Abstract
Background: Succinate Dehydrogenase (SDH) subunit pathogenic variants predispose to Pheochromocytoma and Paraganglioma (PPGL). Functional imaging harnesses the innate receptor expression and the aberrant cellular pathways in PPGLs to improve diagnostic accuracy & guide treatments, including nuclear medicine therapies. Currently commonly available functional imaging modalities include 18F-FDG PET, 123I-MIBG and 68Ga-DOTATATE. Aims: To analyze the use of 123I-MIBG, 18F-FDG PET and 68Ga-DOTATATE in patients harboring SDHB & SDHD pathogenic variants and determine the detection rates for both primary tumors and metastatic sites of disease. Methods: Retrospective review of patient records and imaging reports allowed tumor characteristics and imaging features of 21 patients with SDH-related PPGL to be recorded. Contrast enhanced CT/MRI were used as control to calculate the sensitivity of each functional imaging modality. Avidity of the primary lesion and metastatic deposits were used to calculate detection rates. 123I-MIBG imaging was available for 22 primary tumors (8 SDHB, 14 SDHD), 18FDG-PET for 24 (9 SDHB, 15 SDHD) and 68Ga-DOTATATE for 6 (2 SDHB, 4 SDHD) respectively. Results: 29 PPGLs (primary and metastases, 13 SDHB, 16 SDHD) were identified in 21 patients. 123I-MIBG detected 14/22 (64%) primary tumors; 5/8 (63%) SDHB and 9/14 (64%) SDHD-related PPGL. According to tumor location, 3/3 PCCs, 6/8 HNPGLs and 4/11 non-HNPGLs demonstrated 123I-MIBG avidity. Both18F-FDG PET and 68Ga-DOTATATE detected all PPGLs imaged; 24 (9 SDHB, 15 SDHD) and 6 (2 SDHB, 4 SDHD) respectively, demonstrating 100% sensitivity in the detection of the primary PPGL in all the above locations. 6 metastatic deposits (located in bone, lungs, liver and local lymph nodes) in 4 patients were imaged using all 3 modalities (3 SDHB, 1 SDHD), all of which were avid on 18F-FDG PET and 68Ga-DOTATATE whereas only 50% demonstrated avidity on 123I-MIBG imaging. Discussion: Recent guidelines promote preferential use of 68Ga-DOTATATE and 18F-FDG PET as initial functional imaging modalities in SDHx-related disease over 123I-MIBG. The results from our patient cohort indicate superior sensitivity (100%) for detection of SDHx-related disease with FDG and Dotatate compared with MIBG. In contrast to the current literature, a high proportion (75%) of HNPGLs in our series demonstrated MIBG avidity. Further prospective studies are needed to further evaluate these and various other novel tracers to inform diagnostic and therapeutic strategy in PPGLs arising from SDHx and various other germline and somatic pathogenic variants.
A Rare Case Report of Acquired Bartters With Positive Anti Scl70 Antibody
Authors: Pande Arunkumar Ramanarth , Mohanty Deepali 
Published: May 2021

Abstract
Introduction: Bartter syndrome autosomal recessive renal tubular disorders usualy presents in infant age group or antenatallyCase Description64 years housewife, a known case of hypothyroidism with in emergency with generalized weakness and hypotension. She had an small adrenal nodule work up which showed that it was non functional. On evaluation at time of stress (blood pressure 70/50) her serum cortisol was 300nmol/l and she was therefore started on hydrocortisone. Her records revealed hypokalemia for last 2 years. Workup of hypokalemia showed kaliuresis, metabolic alkalosis, hypercalciuria and excess chloride excretion in the urine, suggestive of bartter’s syndrome. But this needed further confirmation as bartter’s is rare in this age group and also the test was done at the time of stress. She was started on spironolactone and oral potassium supplementation. CECT head done for evaluation of postural dizziness showed chronic cortical venous thrombosis. On follow up ACTH stimulated cortisol was done which showed normal cortisol level so steroid was stopped. She was readmitted one month later with hypokalemia(K-1.8 meq/l) while being on same dosage of spironolactone and potassium. Workup of hypokalemia showed same feature of bartter’s syndrome. Considering the chain of events, a suggestion of bartter’s and response to steroid, a diagnosis of acquired autoimmune bartter’s syndrome along with hypothyroidism was made. An autoimmune work up showed anti SCL 70 positive2+(++). Patient responded to steroid, spironolactone, indomethacin and oral potassium supplementation. Discussion: Bartter’s syndrome can rarely happen in old age too. Seek for autoimmune cause once we suspect acquired bartter’s. To best of our knowledge previously only one case has been reported of acquired Bartter with systemic sclerosis. Patient may develop systemic sclerosis in future as anti SCL70 antibody is very specific for it. It is positive in less than 1 % of general population. Anti SCL70 antibody is rarely positive in Sjogrens syndrome. Our patient did not feature of sjogren or systemic sclerosis even after 4 years follow up
A Case of Paraneoplastic Cushing’s Syndrome in Recurrent Squamous Cell Carcinoma
Authors: Goettemoeller Travis , Tsushima Yumiko , Madhun Nabil Zuhayr , Olansky Leann 
Published: May 2021

Abstract
Background: Ectopic production of ACTH causing Cushing’s syndrome (CS) is rare but has been well described in association with bronchial carcinoids, thymomas, pancreatic malignancies, and small cell lung carcinomas. We report a rare case of CS caused by ACTH-producing non-small cell carcinoma.
Clinical Case: A 71 year-old man with a history of squamous cell carcinoma of the lung (T2bN1M0) 10 years prior who underwent lobectomy and adjunctive chemotherapy, presented with a new cough, weight loss, and bilateral lower extremity edema. He was also noted to have significant fatigue, hypertension, symptomatic hyperglycemia, and hypokalemia. CT chest revealed a large right perihilar mass with mediastinal adenopathy and numerous hepatic lesions.
A biopsy of the liver lesions revealed a poorly differentiated carcinoma with neuroendocrine features strongly positive for AE1/3 with focal p40+, CK7, synaptophysin, chromogranin, and TTF1. It was negative for p63, CK5/6, CDX2, CK20, and GATA3. The morphology and immunohistochemical staining favored a squamous primary. Unfortunately, there was insufficient tissue sample to stain for ACTH. Biochemical evaluation revealed: post-1 mg dexamethasone serum cortisol 74.8 µg/dL (N &lt; 1.8 µg/dL), 24 hr urine free cortisol 2987 µg/g creatinine (normal: &lt; 32 µg/g creatinine), and ACTH 170 pg/mL (N &lt; 47 pg/mL). Other notable findings at presentation were potassium 2.8 mmol/L (N: 3.7-5.1 mmol/L) and glucose 371 mg/dL (N: 74-99 mg/dL). MRI brain revealed focal pituitary infundibular thickening up to 6 mm in diameter and an enlargement of the pituitary gland concerning for metastasis. The patient’s clinical course was complicated by persistent hypokalemia and hyperglycemia which were treated with spironolactone 100 mg twice a day and insulin therapy, respectively. Ketoconazole 100 mg twice a day was initiated for the hypercortisolemia; etoposide, carboplatin, and atezolizumab were started for the neuroendocrine tumor. The patient expired due to sepsis one month after the diagnosis of Cushing’s syndrome. Conclusion: We report a rare case of paraneoplastic Cushing’s syndrome due to poorly differentiated neuroendocrine tumor with a squamous cell carcinoma primary. ACTH producing non-small cell carcinomas have been seldom reported in the literature. Although we were unable to provide ACTH staining on pathology, the existence of an obvious neuroendocrine tumor, marked elevation in ACTH, and an MRI which was negative for a pituitary adenoma, strongly suggests paraneoplastic Cushing’s syndrome.
Biochemical and Genomic Changes of a Devastating Metastatic Medullary Thyroid Cancer
Authors: Soe Myat Han , Liu Chienying , Neinstein Aaron Barak , Murphy Elizabeth J 
Published: May 2021

Abstract
Introduction: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of thyroid parafollicular C cells. About 25% of cases are hereditary, associated with MEN2 syndromes. RET M918 mutation (somatic or germline) is associated with the most aggressive form of MTC. If MTC is hereditary, further tumor genomic analysis is not routinely performed. Therefore, the somatic mutational landscape of hereditary MTCs is not frequently described in the literature. We present an unusual case of MTC with a germline M918 RET mutation, displaying an initial smoldering course followed by rapidly fatal widespread metastases. Whole exome sequencing (WES) of primary tumor and metastases revealed intertumoral heterogeneity with many somatic mutations including p53 mutation.
Clinical Case: The patient with characteristic facies of MEN 2B presented with a neck mass at age 28. She had no family history of MEN. At diagnosis, calcitonin was 11,392 pg/mL and CEA was 729.7 ug/L. Pathology showed MTCs of 5 cm (right) and 2.1 cm (left) with lymph node metastases (pT3N1bMx). Genetic testing showed RET M918 mutation. Postoperative calcitonin and CEA were 3.3 pg/ml and 1.7 ug/L respectively. Tumor markers doubling time was initially about 1 year, but progressively shortened over time. Three years after surgery, calcitonin and CEA were 101 pg/ml and 387 ug/L respectively. CT chest and abdomen identified no distant metastasis. Over the next 4 months, calcitonin and CEA increased dramatically to 1821pg/ml and 3974 ug/L. The patient was admitted for acute liver failure and passed away. Autopsy revealed widely metastatic disease to liver, lungs, spleen, pituitary, right adrenal gland, bones, and brain. WES revealed 87, 283 and 591 somatic mutations in the primary tumor, lung and liver metastases respectively. The primary tumor had chromosome 1p loss whereas liver and lung metastases had somatic mutation of TP53 and single copy loss of chromosome 17 (biallelic inactivation of p53).
Conclusion: This case illustrates intertumoral spatial and temporal genetic heterogeneity. Mutations detected by WES may or may not be cancer-related and their clinical relevance is often uncelar. We hypothesize TP53 biallelic loss might have contributed to the aggressive phenotype of this tumor. Also of note, even before the appearance of metastases, CEA was disproportionately higher than calcitonin, reflecting tumor dedifferentiation. Further studies are needed to address CEA threshold for additional imaging and imaging modality for early detection of metastases.
Glucagonoma: “A Diagnostic Challenge”
Authors: Shah Aashka M , Thumma Soumya , Stout Jessica , Thandassery Ragesh , Williams-Wuch Kerry , Burdine Lyle , Jackman Kimberly , Ambrogini Elena 
Published: May 2021

Abstract
Introduction: Glucagonoma is a rare pancreatic α-islet cell tumor accounting for nearly 1% of all the neuroendocrine tumors (NET), with an incidence of 1 in 20 million people. We present here a patient with glucagonoma with uncontrolled diabetes mellitus (DM) for over ten years and necrolytic migratory erythema (NME) for two years. Clinical Case: A 50-year-old Caucasian male was referred to the endocrinology team for uncontrolled DM type 2. The DM was diagnosed over 10 years prior with initial HbA1c of 10.2% and remained uncontrolled with HbA1c &gt;9%, despite compliance with lifestyle modifications and treatment with multiple agents including metformin, glipizide, empagliflozin, and pioglitazone. Given poor glycemic control, the treatment was escalated to glargine and lixisenatide. Over the years, the patient presented with unintentional weight loss of 105 pounds, fatigue, normocytic normochromic anemia, and diffuse erythematous rash with plaques and scaling on the trunk, flexor surfaces of lower and upper extremities, soles of hands and feet. Punch biopsy of the lesions revealed neutrophilic infiltration. He denied diarrhea, deep venous thrombosis, pulmonary embolism, psychiatric symptoms, or family history of neuroendocrine tumor (NET) or MEN 1 syndrome. A CT chest abdomen and pelvis revealed a 5 cm mass on the pancreatic tail along with liver metastasis. The biopsy confirmed a well-differentiated NET. Serum glucagon and chromogranin-A levels were elevated at 2967 pg/mL (N: 50-150 pg/mL) and 263.8 ng/mL (N: 0-101.8 ng/mL) respectively, consistent with pancreatic glucagonoma. Octreoscan revealed diffuse uptake in the liver, omentum, and spleen. He was started on Octreotide injections monthly, followed by distal pancreatectomy, splenectomy, hepatic wedge resection, and excision of the omental implant with the plan to treat the residual liver metastasis with radioembolization. Pathology analysis showed local invasion and metastasis to local lymph nodes with immunostaining positive for AE1/3, synaptophysin, chromogranin, and Ki67 index &lt;2% consistent with Grade I well-differentiated NET. Post-surgery, serum glucagon and chromogranin-A levels dropped to 400 pg/mL and 68.8 ng/mL respectively. Insulin requirements markedly dropped with an improvement in glycemic control and resolution of the rash. Conclusions: Glucagonoma is an uncommon, slow-growing pancreatic neoplasm resulting in excessive glucagon secretion and it is characterized by diabetes mellitus, NME, chronic diarrhea, and deep vein thrombosis. Nearly 50% of glucagonomas are metastatic at the time of diagnosis. Patients without metastasis have a 10-year survival rate of almost 100%, compared with 51.6% of patients with metastasis, emphasizing the importance of early diagnosis and multidisciplinary treatment approach to achieve a better therapeutic outcome.