Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1

Cancer therapeutics: Extending a drug's reach A new drug that blocks heat shock proteins (HSPs), helper proteins that are co-opted by cancer cells to promote tumor growth, shows promise for cancer treatment. Several drugs have targeted HSPs, since cancer cells are known to hijack these helper proteins to shield themselves from destruction by the body. However, the drugs have had limited success. Hye-Kyung Park and Byoung Heon Kang at Ulsan National Institutes of Science and Technology in South Korea and coworkers noticed that the drugs were not absorbed into mitochondria, a key cellular compartment, and HSPs in this compartment were therefore not being blocked. They identified a new HSP inhibitor that can reach every cellular compartment and inhibit all HSPs. Testing in mice showed that this inhibitor effectively triggered death of tumor cells, and therefore shows promise for anti-cancer therapy. The Hsp90 family proteins Hsp90, Grp94, and TRAP1 are present in the cell cytoplasm, endoplasmic reticulum, and mitochondria, respectively; all play important roles in tumorigenesis by regulating protein homeostasis in response to stress. Thus, simultaneous inhibition of all Hsp90 paralogs is a reasonable strategy for cancer therapy. However, since the existing pan-Hsp90 inhibitor does not accumulate in mitochondria, the potential anticancer activity of pan-Hsp90 inhibition has not yet been fully examined in vivo. Analysis of The Cancer Genome Atlas database revealed that all Hsp90 paralogs were upregulated in prostate cancer. Inactivation of all Hsp90 paralogs induced mitochondrial dysfunction, increased cytosolic calcium, and activated calcineurin. Active calcineurin blocked prosurvival heat shock responses upon Hsp90 inhibition by preventing nuclear translocation of HSF1. The purine scaffold derivative DN401 inhibited all Hsp90 paralogs simultaneously and showed stronger anticancer activity than other Hsp90 inhibitors. Pan-Hsp90 inhibition increased cytotoxicity and suppressed mechanisms that protect cancer cells, suggesting that it is a feasible strategy for the development of potent anticancer drugs. The mitochondria-permeable drug DN401 is a newly identified in vivo pan-Hsp90 inhibitor with potent anticancer activity

In Vitro Macrophage Assay Predicts the In Vivo Anti-inflammatory Potential of Exosomes from Human Mesenchymal Stromal Cells

Extracellular vesicles (EVs) play key roles in cell biology and may provide new clinical diagnostics and therapies. However, it has proven difficult to develop protocols for their purification and characterization. One of the major barriers in the field has been a lack of convenient assays for their bioactivity. Developing assays has not been a trivial matter, because of the heterogeneity of EVs, the multiple activities they demonstrate, and the uncertainty about their modes of action. Therefore, it is likely that multiple assays for their activities are needed. One important assay will be for the anti-inflammatory activity observed in mice after administration of the small EVs commonly referred to as exosomes. We developed an assay for the anti-inflammatory activity of exosomes with a line of mouse macrophages. The assay makes it possible to rank different preparations of exosomes by their anti-inflammatory activity, and their ranking predicts their efficacy in suppressing LPS-stimulated inflammation in mice. The assay is convenient for comparing multiple samples and, therefore, should be useful in developing protocols for the purification and characterization of anti-inflammatory exosomes.Fil: Pacienza, Natalia Alejandra. Texas A&M University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Lee, Ryang Hwa. Texas A&M University; Estados UnidosFil: Bae, Eun-Hye. Texas A&M University; Estados UnidosFil: Kim, Dong-ki. Texas A&M University; Estados UnidosFil: Liu, Qisong. Texas A&M University; Estados UnidosFil: Prockop, Darwin J.. Texas A&M University; Estados UnidosFil: Yannarelli, Gustavo Gabriel. Texas A&M University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentin

Life-Threatening Acute Hyponatremia with Generalized Seizure Induced by Low-Dose Cyclophosphamide in a Patient with Breast Cancer

Cyclophosphamide is commonly used in the treatment of malignant diseases. Symptomatic severe hyponatremia induced by low-dose cyclophosphamide is very uncommon worldwide. Recently we experienced a case of a 56-year-old woman with breast cancer who developed severe hyponatremia with generalized seizure after the first cycle of adjuvant chemotherapy with doxorubicin and cyclophosphamide. Her laboratory test showed a serum sodium of 116 mmol/L. Her hyponatremia was initially treated with hypertonic saline solution and furosemide. She completely recovered without neurological deficits after slow correction of the serum sodium concentration over two days. Clinicians must always keep in mind that life-threatening acute hyponatremia can be induced by intravenous cyclophosphamide during chemotherapy, even if the dosage is low

Does Tumor Size Influence the Diagnostic Accuracy of Ultrasound-Guided Fine-Needle Aspiration Cytology for Thyroid Nodules?

Background. Fine-needle aspiration cytology (FNAC) is diagnostic standard for thyroid nodules. However, the influence of size on FNAC accuracy remains unclear especially in too small or too large thyroid nodules. The objective of this retrospective cohort study was to investigate the effect of nodule size on FNAC accuracy. Methods. All consecutive patients who underwent thyroidectomy for nodules in 2010 were enrolled. FNAC results (according to the Bethesda system) were compared to pathological diagnosis. The nodules were categorized into groups A–E on the basis of maximal diameter on ultrasound (≤0.5, >0.5–1, >1-2, >2–4, and >4 cm, resp.). Results. There were 502 cases with 690 nodules. Overall FNAC sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 95.4%, 98.2%, 99.4%, 86.4%, and 96.0%, respectively. False-negative rates (FNRs) of groups A–E were 3.2%, 5.1%, 1.3%, 13.3%, and 50%, respectively. Accuracy rates of groups A–E were 96.8%, 94.8%, 99%, 94.7%, and 87.5%, respectively. Conclusion. Although accuracy rates of FNAC in thyroid nodules smaller than 0.5 cm are comparable to the other group, thyroid nodules larger than 4 cm with benign cytology carry a higher risk of malignancy, which suggest that those should be considered for intensive follow-up or repeated biopsy

Idiopathic erythrocytosis in a patient on chronic hemodialysis

AbstractA 78-year-old man on hemodialysis presented to our hospital with erythrocytosis. He had started hemodialysis 4 years previously, with a hemoglobin level of 9.8g/dL, and was administered erythropoiesis stimulating agents and ferrous sulfate. Two years previously, his hemoglobin level increased to 14.5g/dL and the treatment for anemia was discontinued. He continued hemodialysis thrice weekly; however, the hemoglobin level had increased to 17.0g/dL at the time of presenting to our hospital. His serum erythropoietin level was 31.4mIU/mL (range, 3.7–31.5mIU/mL), carboxyhemoglobin level was 0.6% (range, 0–1.5%), and oxygen saturation in ambient air was 95.4%. The JAK2 V617F mutation was not observed and other bone marrow abnormalities were not identified. The patient was diagnosed with bladder cancer and a transurethral resection was performed. Eight months after the treatment of bladder cancer, his hemoglobin level was 15.1g/dL, and he was diagnosed with idiopathic erythrocytosis

Multiplicity of Advanced T Category–Tumors Is a Risk Factor for Survival in Patients with Colorectal Carcinoma

Background Previous studies on synchronous colorectal carcinoma (SCRC) have reported inconsistent results about its clinicopathologic and molecular features and prognostic significance. Methods Forty-six patients with multiple advanced tumors (T2 or higher category) who did not receive neoadjuvant chemotherapy and/or radiotherapy and who are not associated with familial adenomatous polyposis were selected and 99 tumors from them were subjected to clinicopathologic and molecular analysis. Ninety-two cases of solitary colorectal carcinoma (CRC) were selected as a control considering the distributions of types of surgeries performed on patients with SCRC and T categories of individual tumors from SCRC. Results SCRC with multiple advanced tumors was significantly associated with more frequent nodal metastasis (p = .003) and distant metastasis (p = .001) than solitary CRC. KRAS mutation, microsatellite instability, and CpG island methylator phenotype statuses were not different between SCRC and solitary CRC groups. In univariate survival analysis, overall and recurrence-free survival were significantly lower in patients with SCRC than in patients with solitary CRC, even after adjusting for the extensiveness of surgical procedure, adjuvant chemotherapy, or staging. Multivariate Cox regression analysis revealed that tumor multiplicity was an independent prognostic factor for overall survival (hazard ratio, 4.618; 95% confidence interval, 2.126 to 10.030; p < .001), but not for recurrence-free survival (p = .151). Conclusions Findings suggested that multiplicity of advanced T category–tumors might be associated with an increased risk of nodal metastasis and a risk factor for poor survival, which raises a concern about the guideline of American Joint Committee on Cancer’s tumor-node-metastasis staging that T staging of an index tumor determines T staging of SCRC

Ovarian Gynandroblastoma with a Juvenile Granulosa Cell Tumor Component in a Postmenopausal Woman: A Case Report and Literature Review

Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingo-oophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review

Association of appendicular skeletal muscle mass with carotid intima-media thickness according to body mass index in Korean adults

OBJECTIVES The combined effects of obesity and appendicular skeletal muscle (ASM) on atherosclerosis, especially in middleaged populations, remain poorly understood. This cross-sectional study investigated the effects of ASM on carotid intima-media thickness (IMT) according to body mass index (BMI) in middle-aged Korean adults. METHODS Herein, 595 men and 1,274 women aged 30-64 years completed questionnaires and underwent health examinations as part of the Cardiovascular and Metabolic Disease Etiology Research Center cohort. ASM was measured via bioelectrical impedance analysis and adjusted for weight (ASM/Wt). IMT was assessed using B-mode ultrasonography; highest quartile of IMT was defined as gender-specific top quartile of the IMT values. Higher BMIs was defined as a BMI over 25.0 kg/m2 . RESULTS Compared to the highest ASM/Wt quartile, the lowest ASM/Wt quartile was significantly associated with highest quartile of IMT in men with lower BMIs (adjusted odds ratio [aOR], 2.78; 95% confidence interval [CI], 1.09 to 7.13), but not in those with higher BMIs (aOR, 0.59; 95% CI, 0.24 to 1.91). In women, there was no significant association of low skeletal muscle mass with highest quartile of IMT, regardless of BMI. CONCLUSIONS Low appendicular skeletal muscle mass is associated with carotid arterial wall thickening in men with lower BMIs, but not in men with higher BMIs. Our findings suggest that the risk of atherosclerosis may be low in middle-aged Korean men with appropriate body weight and skeletal muscle mass maintenance

Calcified Carcinoma of the Gallbladder with Calcified Nodal Metastasis Presenting as a Porcelain Gallbladder: A Case Report

Porcelain gallbladder is regarded as a risk factor of gallbladder cancer. A porcelain gallbladder with calcified regional lymph nodes was found using computed tomography (CT) and magnetic resonance imaging (MRI) in a 43-year-old man who presented with nausea, vomiting, and abdominal pain. His cholecystectomy specimen showed diffuse wall thickening and contained small gallstones. Histological examination revealed diffuse infiltrative adenocarcinoma with extensive intratumoral calcification (calcified carcinoma). The majority of the calcified material was located within or replaced the tumor glands, and was not found in the stroma. A lymph node was totally replaced with a calcified metastatic adenocarcinoma. To the best of our knowledge, only one case of calcified lymph node metastasis from a calcified carcinoma of the gallbladder has been previously reported in the literature. We herein add a case of calcified carcinoma of the gallbladder with calcified lymph node metastasis, presenting as a porcelain gallbladder on CT and MRI