Therapeutic advances in BIG3‐PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer

Our previous studies demonstrated that specific inhibition of the BIG3‐PHB2 complex, which is a critical modulator in estrogen (E2) signaling, using ERAP, a dominant negative peptide inhibitor, leads to suppression of E2‐dependent estrogen receptor (ER) alpha activation through the reactivation of the tumor suppressive activity of PHB2. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the crosstalk between E2 and growth factors associated with intrinsic or acquired resistance to anti‐estrogen tamoxifen in breast cancer cells. Intrinsic PHB2 released from BIG3 by ERAP effectively disrupted each interaction of membrane‐associated ERα and insulin‐like growth factor 1 receptor beta (IGF‐1Rβ), EGFR, PI3K or human epidermal growth factor 2 (HER2) in the presence of E2 and the growth factors IGF or EGF, followed by inhibited the activation of IGF‐1Rβ, EGFR or HER2, and reduced Akt, MAPK and ERα phosphorylation levels, resulting in significant suppression of proliferation of ERα‐positive breast cancer cells in vitro and in vivo. More importantly, combined treatment with ERAP and tamoxifen led to a synergistic suppression of signaling that was activated by crosstalk between E2 and growth factors or HER2 amplification. Taken together, our findings suggest that the specific inhibition of BIG3‐PHB2 is a novel potential therapeutic approach for the treatment of tamoxifen‐resistant breast cancers activated by the crosstalk between E2 and growth factor signaling, especially in premenopausal women.     

Spontaneous Regression of a Metastatic Liver Tumor: Report of a Case

A 60-year-old man, who suffered from advanced rectal cancer accompanied with liver metastasis, underwent an abdominoperineal resection and a partial hepatectomy. He remained well until 4 months after surgery when he developed a biopsy-proven recurrent intrapelvic mass and multiple liver tumors. At 6 months after surgery, the metastatic liver tumors grew larger and almost completely occupied both lobes of the liver. However, 9 months after surgery, the liver tumors regressed remarkably and his clinical condition improved without any specific treatment for cancer. Although he died of cancerous peritonitis 18 months after surgery, the autopsy findings did not indicate any apparent regrowth of the liver tumors. To date, only one case report of a spontaneous regression of a metastatic liver tumor from colorectal cancer has been published in the English literature. We herein describe this rare case and discuss some of the reasons potentially responsible for the regression. Received: July 16, 2001 / Accepted: March 5, 2002     

Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses

BACKGROUND: Immune regulatory CD4+CD25+ T (regulatory T; Treg) cells play a vital role in the induction and maintenance of self-tolerance. They are essential for the homeostasis of T cells, the prevention of autoimmunity, and the induction of tolerance to allogeneic donor grafts. However, the underlying mechanism of their functions remains mostly elusive. Therefore, we investigated here a crucial role of Treg cells in their response to alloantigen via the programmed death (PD)-1/PD-1 ligand (PD-L1) pathway. METHODS: In vitro mixed lymphocyte reaction (MLR) assay, graft-versus-host disease (GvHD) and a skin transplantation model were used to evaluate the mechanisms of PD-1/PD-L1 pathway. RESULTS: Blockade of the PD-1/PD-L1 pathway using anti-PD-L1 monoclonal antibodies (mAb) is found to inhibit Treg cell's ability to suppress and restore CD4+CD25-T-cell proliferation in vitro. GvHD was lethal after adoptive transfer of allogeneic C57BL/6 (H-2K) spleen cells to NOD/SCID (H-2K) mice unless CD25+ T cells were also included. Strikingly, the suppression of GvHD by CD25+ cells was abrogated by anti-PD-L1 mAb administration. The abrogation of Treg-cell-mediated suppression could also be demonstrated in a Balb/c (H-2K) to B6/Rag-2KO (H-2K) skin-allograft model. CONCLUSIONS: The blockade of the PD-1/PD-L1 pathway abrogates Treg-mediated immunoregulation, thus suggesting that the PD-1/PD-L1 pathway is required for Treg suppression of the alloreactive responses of CD4+CD25-T cells. This finding has important implications for clarifying the mechanisms of allograft rejection and GvHD.     

Management of pancreatic mass accompanying chronic pancreatitis

We report two patients with focal, chronic pancreatitis that was diagnosed by dynamic computed tomography (CT) combined with intraoperative biopsy. In case 1, serum carbohydrate antigen (CA) 19-9 level rose to 160 U/ml. Abdominal ultrasonography, CT, and magnetic resonance imaging demonstrated a mass, of 4.5 cm in diameter, in the pancreatic head. On dynamic CT, the mass was enhanced similarly to the normal pancreatic parenchyma. In case 2, dynamic CT demonstrated a mass, of 3.0 cm in diameter, in the pancreatic head, which was enhanced similarly to the normal pancreatic parenchyma. From such characteristics of enhancement, both masses were suspected to be chronic pancreatitis rather than cancer, and the diagnosis was confirmed by intraoperative biopsy. Three years in case 1 and 2 years in case 2 have passed since their operations, and the size of each mass has not changed. With the use of dynamic CT combined with intraoperative biopsy, focal chronic pancreatitis could be diagnosed more accurately, and this may lead to a reduction in unnecessary pancreatic resection. Received: November 16, 2001 / Accepted: February 8, 2002     

Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases

OBJECTIVE: To better determine the role of portal vein resection and its effect on survival, as well as to appreciate the impact of portal vein invasion on prognosis in hilar cholangiocarcinoma. SUMMARY BACKGROUND DATA: Hepatectomy with portal vein resection is sometimes performed for locally advanced hilar cholangiocarcinoma. However, the significance of microscopic invasion of the portal vein has not been determined. METHODS: Medical records of 160 patients with hilar cholangiocarcinoma who underwent macroscopically curative hepatectomy with (n = 52) or without portal vein resection (n = 108) were reviewed. Invasion of the portal vein was assessed histologically on the surgical specimen, and results were correlated with clinicopathologic features and survival. RESULTS: Surgical mortality, including all hospital deaths, was similar in patients who did and did not undergo portal vein resection (9.6% vs. 9.3%), but the primary tumor was more advanced in patients who underwent portal vein resection. Histologically, no invasion was found in 16 (30.8%) of resected portal veins. However, dense fibrosis adjacent to the portal vein was common, and the mean distance between the leading edge of cancer cells and the adventitia of the portal vein was 437 +/- 431 mum. The prognosis was worse in patients with than without portal vein resection (5-year survival, 9.9% vs. 36.8%; P < 0.0001). The presence or absence of microscopic invasion of the resected portal vein did not influence survival (16.6 months in patients with microscopic invasion vs. 19.4 months in those without; P = 0.1506). Multivariate analysis identified histologic differentiation, lymph node metastasis, and macroscopic portal vein invasion as independent prognostic factors. CONCLUSIONS: Microscopic invasion of the portal vein may be misdiagnosed clinically in patients with hilar cholangiocarcinoma. However, the distance between tumor and adventitia is so narrow that curative resection without portal vein resection is unlikely to be possible. Gross portal vein invasion has a negative impact on survival, and hepatectomy with portal vein resection can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.     

Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition

Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models.Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993     

Recent advances in the treatment of hilar cholangiocarcinoma: portal vein embolization

The clinical application of portal vein embolization (PVE) has contributed to improving the postoperative outcome of hilar cholangiocarcinoma. The enlarged nonembolized lobe after PVE protects the patient from postoperative hepatic failure, due to the increased functional reserve, and shortens the hospital stay. Although numerous reports have shown beneficial effects of PVE on postoperative outcome after extended hepatectomy, no randomized controlled study has been performed so far. It is urgent to establish a “gold standard” of PVE, because the indications, approach to the portal vein, types of embolic materials, and methods used to evaluate the function of the future liver remnant are variable among institutions. The indications and procedures of PVE for hilar cholangiocarcinoma may be different from those for hepatocellular carcinoma or colorectal metastasis, because, in many patients with hilar cholangiocarcinoma, biliary cancer is associated with biliary obstruction and cholangitis. This review article summarizes the contribution of PVE to the outcome of postoperative management in patients with hilar cholangiocarcinoma needing extended hepatectomy. We also describe our PVE procedure, which has been established from our experience of more than 240 cases of biliary cancer. Furthermore, the drawbacks of PVE, which may reduce the pool of candidates for surgery, are also discussed.