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

MHC class II engagement inhibits CD99-induced apoptosis and up-regulation of T cell receptor and MHC molecules in human thymocytes and T cell line

AbstractMajor histocompatibility complex (MHC) class II surface levels on thymocytes increase after CD99 ligation. The functional implication of the up-regulated MHC class II was assessed by engaging MHC class II on CD99-ligated cells. MHC class II engagement down-modulated surface levels of T cell receptor and MHC molecules, and inhibited apoptosis of CD99-ligated thymocytes and CEM tumor cells, antagonistic effects on the previously reported CD99 functions. The results were reproducible regardless of the order of ligation of MHC class II and CD99. We suggest that signaling via MHC class II on CD99-engaged cells might be involved in the thymic maturation process by damping CD99 ligation effects

A single gene of a commensal microbe affects host susceptibility to enteric infection

Indigenous microbes inside the host intestine maintain a complex self-regulating community. The mechanisms by which gut microbes interact with intestinal pathogens remain largely unknown. Here we identify a commensal Escherichia coli strain whose expansion predisposes mice to infection by Vibrio cholerae, a human pathogen. We refer to this strain as 'atypical' E. coli (atEc) because of its inability to ferment lactose. The atEc strain is resistant to reactive oxygen species (ROS) and proliferates extensively in antibiotic-treated adult mice. V. cholerae infection is more severe in neonatal mice transplanted with atEc compared with those transplanted with a typical E. coli strain. Intestinal ROS levels are decreased in atEc-transplanted mice, favouring proliferation of ROS-sensitive V. cholerae. An atEc mutant defective in ROS degradation fails to facilitate V. cholerae infection when transplanted, suggesting that host infection susceptibility can be regulated by a single gene product of one particular commensal species.

A multicenter, prospective, randomized, controlled trial evaluating the safety and efficacy of intracoronary cell infusion mobilized with granulocyte colony-stimulating factor and darbepoetin after acute myocardial infarction: study design and rationale of the 'MAGIC cell-5-combination cytokine trial'

<p>Abstract</p> <p>Background</p> <p>Bone marrow derived stem/progenitor cell transplantation after acute myocardial infarction is safe and effective for improving left ventricular systolic function. However, the improvement of left ventricular systolic function is limited. This study will evaluate novel stem/progenitor cell therapy with combination cytokine treatment of the long-acting erythropoietin analogue, darbepoetin, and granulocyte colony-stimulating factor (G-CSF) in patients with acute myocardial infarction.</p> <p>Methods</p> <p>The 'MAGIC Cell-5-Combination Cytokine Trial' is a multicenter, prospective, randomized, 3-arm, controlled trial with blind evaluation of the endpoints. A total of 116 patients will randomly receive one of the following three treatments: an intravenous darbepoetin infusion and intracoronary infusion of peripheral blood stem cells mobilized with G-CSF (n = 58), an intracoronary infusion of peripheral blood stem cells mobilized with G-CSF alone (n = 29), or conventional therapy (n = 29) at phase I. Patients with left ventricular ejection fraction < 45% at 6 months, in the patients who received stem cell therapy at phase I, will receive repeated cell therapy at phase II. The objectives of this study are to evaluate the safety and efficacy of combination cytokine therapy with erythropoietin and G-CSF (phase I) and repeated progenitor/stem cell treatment (phase II).</p> <p>Discussion</p> <p>This is the first study to evaluate the safety and efficacy of combination cytokine based progenitor/stem cell treatment.</p> <p>Trial registration</p> <p><url>http://www.ClinicalTrials.gov</url> identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00501917">NCT00501917</a>.</p

Percutaneous radiofrequency ablation for hepatic tumors: factors affecting baseline impedance

PurposeWe aimed to evaluate factors that affect baseline impedance of percutaneous radiofrequency ablation.MethodsIn this retrospective study, we analyzed 51 patients with 55 hepatic tumors from November 2015 until April 2018. We measured the baseline impedance nine times with three adjustable tip sizes (2 cm, 2.5 cm, 3 cm) and three different pad locations (two pads attached on the thigh, four on the thigh, two on the back). The first roll-off time was measured with two grounding pads attached on the back. Body mass index, cirrhotic or non-cirrhotic liver parenchyma, previous procedure, tumor location, artificial ascites, active tip size, and the pad location were evaluated as potential factors affecting baseline impedance using the Mann–Whitney U test, t-test and analysis of variance test.ResultsComplete radiofrequency ablation was achieved in 51 patients. Body mass index (p = 0.897), cirrhotic or non-cirrhotic liver parenchyma (p = 0.767), previous procedure (p = 0.957), tumor location (p = 0.906), and artificial ascites (p = 0.882) did not significantly affect baseline impedance. Grounding pads located on the back showed the lowest baseline impedance (p < 0.001). Increase in active tip size showed gradual decrease in baseline impedance (p = 0.016).ConclusionThe factors affecting baseline impedance were the pad location and the tip size. Positioning pads on the back lowers the baseline impedance and can shorten the first roll-off time, ultimately resulting in reduced total ablation time

Phlegmonous Enteritis in a Patient with Congestive Heart Failure and Colon Cancer

Phlegmonous enteritis is a rare infective inflammatory disease of the intestine, predominantly involving the submucosal layer. It is difficult to diagnose and often fatal. Its association with alcoholism and various liver diseases, although rarely reported, is well documented. We report a case of phlegmonous enteritis in a male patient with congestive heart failure and colon cancer, and describe the ultrasonographic and CT findings

Two cases of female hydrocele of the canal of nuck

The processus vaginalis within the inguinal canal forms the canal of Nuck, which is a homolog of the processus vaginalis in women. Incomplete obliteration of the processus vaginalis causes indirect inguinal hernia or hydrocele of the canal of Nuck, a very rare condition in women. Here, we report 2 cases of hydrocele of the canal of Nuck that were diagnosed with ultrasonography in both cases and magnetic resonance imaging in 1 case to confirm the sonographic diagnosis. High ligation and hydrocelectomy were conducted in both patients. In 1 patient, 14 months later, the occurrence of contralateral inguinal hernia was suspected, but did not require surgery. The other patient had a history of surgery for left inguinal hernia 11 months before the occurrence of right hydrocele of the canal of Nuck. In both cases, the occurrence of an inguinal hernia on the contralateral side was noted

KITENIN increases invasion and migration of mouse squamous cancer cells and promotes pulmonary metastasis in a mouse squamous tumor model

AbstractKAI1 C-terminal interacting tetraspanin (KITENIN) is reported to promote metastasis in mouse colon cancer models. We investigated the role of KITENIN on the progression of squamous cell carcinoma (SCC). In a preliminary clinical study using resected tissues from head and neck SCC patients, KITENIN was highly expressed in tumors and metastatic lymph nodes, while KAI1 was more increased in adjacent mucosa than in tumor. KITENIN-transfected mouse squamous cancer (SCC VII/KITENIN) cells showed significantly higher invasion, migration, and proliferation than empty vector-transfected cells. In syngeneic mouse squamous tumor models, more increased tumor volume and enhanced lung metastasis were found in SCC VII/KITENIN cells-injected mice. Thus, KITENIN increases invasion and migration of squamous cancer cells and thereby promotes distant metastasis in mouse squamous tumor models