Surgical outcomes of patients with acute cholecystitis treated with gallbladder drainage followed by early cholecystectomy.

AIM: This study aimed to investigate the impact of preoperative gallbladder drainage and the specific drainage method used on surgical outcomes in patients undergoing surgery for acute cholecystitis. METHODS: This single-center retrospective cohort study included 221 patients who underwent early cholecystectomy between January 2016 and December 2020. Clinical data and outcomes of 140 patients who did not undergo drainage, 22 patients who underwent preoperative percutaneous transhepatic gallbladder drainage (PTGBD), and 59 patients who underwent preoperative endoscopic naso-gallbladder drainage (ENGBD) were compared. RESULTS: There was no difference in the operation time, blood loss, postoperative complications, or length of postoperative hospital stay between patients who did and did not undergo drainage. Among patients who underwent drainage, there was no difference between the ENGBD and PTGBD groups in operation time, blood loss, or postoperative complications; however, more patients in the PTGBD group underwent laparotomy and had a significantly longer postoperative hospital stay. The presence and type of drainage were not risk factors for postoperative complications. CONCLUSION: The presence or absence of preoperative gallbladder drainage for acute cholecystitis and the type of drainage may not significantly affect surgical outcomes.

Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling.

Cancer stem cells (CSCs), which are critical targets for cancer therapy as they are involved in drug resistance to anticancer drugs, and metastasis, are maintained by angiocrine factors produced by particular niches that form within tumor tissue. Secreted frizzled-related protein 1 (Sfrp1) is an extracellular protein that modulates Wnt signaling. However, the cells that produce Sfrp1 in the tumor environment and its function remain unclear. We aimed to elucidate angiocrine factors related to CSC maintenance, focusing on Sfrp1. Although Sfrp1 is a Wnt pathway-related factor, its impact on tumor tissues remains unknown. We investigated the localization of Sfrp1 in tumors and found that it is expressed in some tumor vessels. Analysis of mice lacking Sfrp1 showed that tumor growth was suppressed in Sfrp1-deficient tumor tissues. Flow cytometry analysis indicated that CSCs were maintained in the early tumor growth phase in the Sfrp1 knockout (KO) mouse model of tumor-bearing cancer. However, tumor growth was inhibited in the late tumor growth phase because of the inability to maintain CSCs. Real-time PCR results from tumors of Sfrp1 KO mice showed that the expression of Wnt signaling target genes significantly decreased in the late stage of tumor growth. This suggests that Sfrp1, an angiocrine factor produced by the tumor vascular niche, is involved in Wnt signaling-mediated mechanisms in tumor tissues.

Preoperative diagnosis and safe surgical approach in gallbladder amyloidosis: a case report.

BACKGROUND: Preoperative diagnosis of gallbladder amyloidosis is usually difficult. In our case, the patient exhibited gallbladder dyskinesia, which led us to suspect cholecystic amyloidosis. We were able to safely perform surgery before cholecystitis onset. CASE PRESENTATION: A 59-year-old male patient with a history of multiple myeloma and cardiac amyloidosis presented to our hospital with a chief complaint of epicardial pain. Abdominal ultrasonography and computed tomography revealed an enlarged gallbladder and biliary sludge without any specific imaging findings of cholecystitis. After percutaneous transhepatic gallbladder aspiration (PTGBA), the patient experienced recurrent bile retention and right upper quadrant pain. Flopropione was effective in relieving these symptoms. Based on his symptoms and laboratory findings, we diagnosed the patient with dyskinesia of the gallbladder. Considering his medical history, we suspected that it was caused by amyloidosis of the gallbladder. A laparoscopic cholecystectomy was performed. The histopathological examination showed amyloid deposits in the gallbladder mucosa, from the intrinsic layer to the submucosa, and in the peripheral nerves of the gallbladder neck. The patient was discharged on postoperative day 5 and has had no recurrence of abdominal pain since then. CONCLUSION: In our case, gallbladder dyskinesia symptoms led us to suspect gallbladder amyloidosis. We safely surgically treated the patient before cholecystitis onset.

Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study.

Background: In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. Materials and methods: This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5 ml/body weight 1 kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. Conclusion: This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.

Peritoneal dissemination of appendiceal goblet cell adenocarcinoma mimicking white pus caused by peritonitis following appendicitis: an instructive case report.

BACKGROUND: Goblet cell adenocarcinoma is an extremely rare tumor in which the same cells exhibit both mucinous and neuroendocrine differentiation. It is considered more aggressive compared to conventional carcinoids and more likely to cause metastasis. CASE PRESENTATION: We report a case of goblet cell adenocarcinoma with peritoneal metastases. A 62-year-old man underwent appendectomy for acute appendicitis. Intraoperatively, inflammatory white pus and a small amount of dirty ascites were observed in the lower abdomen with severely inflamed appendix. Histopathological examination of the specimen collected during appendectomy revealed goblet cell adenocarcinoma with a positive surgical margin. One month later, additional ileal resection was planned. Laparoscopic examination revealed disseminated nodules throughout the abdominal cavity. Therefore, the patient underwent resection of the peritoneal nodules. The peritoneal specimens confirmed the histopathological findings. Thus we diagnosed the patient with peritoneal dissemination of appendiceal goblet cell adenocarcinoma. CONCLUSIONS: In cases wherein white pus is observed during surgery for acute appendicitis, considering the possibility of dissemination, collecting samples for histopathological examination, and initiating early treatment are crucial.

Prognostic impact of pre- and postoperative tumor markers in patients with intrahepatic cholangiocarcinoma.

PURPOSE: The present study assessed the impact of pre- and postoperative tumor markers on the survival of patients with intrahepatic cholangiocarcinoma. METHODS: Medical records of 73 patients with intrahepatic cholangiocarcinoma were reviewed retrospectively. The pre- and postoperative carcinoembryonic antigen and carbohydrate antigen 19-9 levels were assessed. Patient characteristics, clinicopathological factors, and prognostic factors were analyzed. RESULTS: The median recurrence-free survival and overall survival were 30.0 and 90.9 months, respectively. A multivariate survival analysis revealed that elevated postoperative carbohydrate antigen 19-9 (p = 0.023) was the only independent poor prognostic factor. The median overall survival of patients with normal and elevated postoperative carbohydrate antigen 19-9 levels was 101.4 and 15.7 months (p < 0.001), respectively. Multivariate logistic regression identified elevated preoperative carbohydrate antigen 19-9 as an independent preoperative risk factor for elevated postoperative carbohydrate antigen 19-9. The optimal cutoff value of preoperative carbohydrate antigen 19-9 for predicting elevated postoperative carbohydrate antigen 19-9 was 40 U/mL, with a sensitivity and specificity of 92% and 87%, respectively (area under curve = 0.915). CONCLUSIONS: Elevated postoperative carbohydrate antigen 19-9 was an independent poor prognostic factor. Preoperative predictors, such as elevated preoperative carbohydrate antigen 19-9, may indicate the need for neoadjuvant therapies to improve the survival.

Comparison of postoperative outcomes in cases achieving sustained virological response with direct-acting antiviral and interferon therapy.

BACKGROUND/PURPOSE: The effect of direct-acting antiviral agents (DAAs) on hepatocellular carcinoma (HCC) recurrence after curative hepatectomy remains uncertain. This retrospective study aimed to evaluate the effect of sustained virological response (SVR) with DAAs or interferon (IFN) therapy on recurrence and overall survival (OS) after hepatectomy. METHODS: We enrolled 593 patients who underwent curative resections between January 2010 and December 2017. Among them, 186 achieved SVR before hepatectomy: a total of 51 (27.4%) in the DAA-SVR group and 132 (72.6%) in the IFN-based SVR group. RESULTS: SVR before hepatectomy was an independent predictor of OS, and the 5-year OS rate was significantly higher in the SVR group than that in the non-SVR group (82.2% vs. 63.9%). There were no significant differences in the recurrence rates or OS between DAA and IFN treatments in achieving SVR before hepatectomy, regardless of poor hepatic function in the DAA therapy group. CONCLUSIONS: There was no significant difference in OS and recurrence-free survival (RFS) between the preoperative SVR achieved with DAA and IFN groups in this study, although liver function was significantly worse at the time of surgery in the DAA group compared to the IFN group.

The efficacy and safety of pure laparoscopic liver resection for hepatocellular carcinoma in super-elderly patients over 80 years: A multicenter propensity analysis.

BACKGROUND: Very few reports have evaluated the safety of laparoscopic liver resection in super-elderly patients. We assessed the short-term outcomes of laparoscopic liver resection in patients with hepatocellular carcinoma aged ≥80 years, using propensity score matching. METHODS: We retrospectively analyzed the data of 287 patients (aged ≥80 years) who underwent liver resection for hepatocellular carcinoma at eight hospitals belonging to Hiroshima Surgical study group of Clinical Oncology, between January 2012 and December 2021. The perioperative outcomes were compared between laparoscopic and open liver resection, using propensity score matching. RESULTS: Of the 287 patients, 83 and 204 were included in the laparoscopic and open liver resection groups, respectively. Propensity score matching was performed, and 52 patients were included in each group. The operation (p = .68) and pringle maneuver (p = .11) time were not different between the groups. There were no significant differences in the incidences of bile leakage or organ failure. The laparoscopic liver resection group had significantly less intraoperative bleeding and a lower incidence of cardiopulmonary complications (both p < .01). CONCLUSIONS: Laparoscopic liver resection can be safely performed in elderly patients aged ≥80 years.

Early embryonic mutations reveal dynamics of somatic and germ cell lineages in mice.

De novo mutations accumulate with zygotic cell divisions. However, the occurrence of these mutations and the way they are inherited by somatic cells and germ cells remain unclear. Here, we present a novel method to reconstruct cell lineages. We identified mosaic mutations in mice using deep whole-genome sequencing and reconstructed embryonic cell lineages based on the variant allele frequencies of the mutations. The reconstructed trees were confirmed using nuclear transfer experiments and the genotyping of approximately 50 offspring of each tree. The most detailed tree had 32 terminal nodes and showed cell divisions from the fertilized egg to germ cell- and somatic cell-specific lineages, indicating at least five independent cell lineages that would be selected as founders of the primordial germ cells. The contributions of each lineage to germ cells and offspring varied widely. At the emergence of the germ cell-specific lineages, 10-15 embryonic mutations had accumulated, suggesting that the pregastrulation mutation rate is 1.0 mutation per mitosis. Subsequent mutation rates were 0.7 for germ cells and 13.2 for tail fibroblasts. Our results show a new framework to assess embryonic lineages; further, we suggest an evolutionary strategy for preserving heterogeneity owing to postzygotic mutations in offspring.

Effects of watercress extract fraction on R-spondin 1-mediated growth of human hair.

OBJECTIVE: Hair loss and greying affect men and women of all ages, often causing psychosocial difficulties. Dickkopf-1 (DKK1), a major hair loss factor secreted from dermal papilla (DP) cells in response to the secretion of dihydrotestosterone (DHT), has been reported to induce and accelerate androgenetic alopecia (AGA). In addition, DKK1 acts as a potent suppressor of melanogenesis and is closely related to hair colour. R-spondin 1 (RSPO1) is a secretory agonist of Wnt signalling known to antagonize the effects of DKK1, including DKK1-mediated hair follicle suppression. In this study, we investigated the effect of watercress extract (WCE) on the secretion of RSPO1 and DKK1 from DP cells as well as its anti-hair loss effect in human hair follicles and patients. METHODS: The in vitro secretion of RSPO1 and DKK1 was measured by ELISA. Human hair follicles were collected from the scalp of a female donor and used for ex vivo organ culture to investigate the effects of WCE on human hair loss. Finally, a 6-month human clinical trial was conducted to examine the effect of WCE-containing lotion on hair growth in a male panel. RESULTS: WCE significantly upregulated RSPO1 secretion and suppressed DKK1 secretion in a dose-dependent manner, even in the presence of DHT. WCE-treated hair follicles elongated 1.6-fold compared with the control, and the level of RSPO1 production in DP as well as RSPO1 bound to the outer root sheath (ORS) increased. In the clinical trial, the hair lotion containing 2% WCE increased hair thickness and density to improve against hair loss symptoms. CONCLUSION: WCE exhibited a strong anti-androgenic effect through its ability to suppress DKK1 secretion and antagonize DKK1 via RSPO1. These findings highlighted the potential use of WCE for the treatment of hair loss.

OBJECTIF: La perte de cheveux et le grisonnement touchent des hommes et des femmes de tous âges, ce qui entraîne souvent des difficultés psychosociales. Selon des rapports, Dickkopf-1 (DKK1), un facteur de perte de cheveux majeur sécrété par les cellules de la papille dermique (PD) en réponse à la sécrétion de dihydrotestostérone (DHT), induit et accélère l'alopécie androgénétique (AAG). En outre, DKK1 agit comme un puissant suppresseur de la mélanogenèse et est étroitement lié à la couleur des cheveux. La protéine R-spondin 1 (RSPO1) est un agoniste sécrétoire de la voie de signalisation Wnt connue pour antagoniser les effets de DKK1, notamment la suppression des follicules pileux médiée par DKK1. Dans cette étude, nous avons étudié l'effet de l'extrait de cresson sur la sécrétion de RSPO1 et de DKK1 à partir des cellules de la PD, ainsi que son effet anti-perte de cheveux sur les follicules pileux humains et chez les patients. MÉTHODES: La sécrétion in vitro de RSPO1 et de DKK1 a été mesurée à l'aide de la méthode ELISA. Des follicules pileux humains ont été prélevés sur le cuir chevelu d'une femme et utilisés pour une culture d'organes ex vivo afin d'étudier les effets de l'extrait de cresson sur la perte de cheveux humains. Enfin, un essai clinique de 6 mois chez l'être humain a été mené pour examiner l'effet d'une lotion contenant de l'extrait de cresson sur la croissance des cheveux au sein d'un panel d'hommes. RÉSULTATS: L'extrait de cresson a significativement régulé à la hausse la sécrétion de RSPO1 et a supprimé la sécrétion de DKK1 de manière dose-dépendante, même en présence de DHT. Les follicules pileux traités avec de l'extrait de cresson ont été multipliés par 1,6 par rapport au groupe témoin, et le niveau de production de RSPO1 dans la PD ainsi que le taux de RSPO1 lié à la gaine externe de la racine ont augmenté. Dans l'essai clinique, la lotion pour cheveux contenant 2 % d'extrait de cresson a augmenté l'épaisseur et la densité des cheveux, améliorant ainsi les symptômes de perte de cheveux. CONCLUSION: La capacité de l'extrait de cresson à supprimer la sécrétion de DKK1 et à antagoniser DKK1 via la protéine RSPO1 lui a conféré un effet anti-androgénique puissant. Ces résultats ont mis en évidence le potentiel de l'extrait de cresson pour le traitement de la perte de cheveux.

Targeting the IGF-Axis Potentiates Immunotherapy for Pancreatic Ductal Adenocarcinoma Liver Metastases by Altering the Immunosuppressive Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy, resistant to chemotherapy and associated with high incidence of liver metastases and poor prognosis. Using murine models of aggressive PDAC, we show here that in mice bearing hepatic metastases, treatment with the IGF-Trap, an inhibitor of type I insulin-like growth factor receptor (IGF-IR) signaling, profoundly altered the local, immunosuppressive tumor microenvironment in the liver, curtailing the recruitment of myeloid-derived suppressor cells, reversing innate immune cell polarization and inhibiting metastatic expansion. Significantly, we found that immunotherapy with anti-PD-1 antibodies also reduced the growth of experimental PDAC liver metastases, and this effect was enhanced when combined with IGF-Trap treatment, resulting in further potentiation of a T-cell response. Our results show that a combinatorial immunotherapy based on dual targeting of the prometastatic immune microenvironment of the liver via IGF blockade, on one hand, and reversing T-cell exhaustion on the other, can provide a significant therapeutic benefit in the management of PDAC metastases.

Usefulness and safety of midline incision for right-sided hepatectomy: Cohort study.

BACKGROUND: While the adoption rates of laparoscopic hepatectomy are increasing, most patients still undergo open hepatectomy. Open hepatectomies use inverted L-shaped or Mercedes incisions for right-sided liver tumor. To decrease procedural invasiveness, we performed midline incisions in such cases, excluding those of laparoscopic hepatectomy. This retrospective study examined the effects of this change in treatment policy on overall patient surgical outcomes. MATERIALS AND METHODS: From 2012 to 2018, 374 patients who underwent hepatectomy for right-sided hepatocellular carcinoma were enrolled, and short-term patient outcomes were compared following stratification into the 1st (n = 157) or 2nd (n = 217) Era group based on whether procedures occurred before or after the policy change, respectively. RESULTS: Short-term outcomes were mostly comparable between the two groups, with significantly increased postoperative aspartate aminotransferase maximum values found in the 2nd Era group relative to the 1st Era group (median: 393 vs. 331, p < 0.05). Pain scores at rest during postoperative day 1 and while moving on postoperative days 1, 2, and 3 were significantly lower in the 2nd Era group than in the 1st Era group (p < 0.05, <0.01, <0.05, <0.01, respectively). CONCLUSIONS: Utilization of midline incisions may provide some benefits in postoperative outcomes for right-sided open hepatectomy cases.

Significance of liver resection for intermediate stage hepatocellular carcinoma according to subclassification.

BACKGROUND: Patients diagnosed with Barcelona Clinic Liver Cancer (BCLC) intermediate stage hepatocellular carcinoma (HCC) encompass a broad clinical population. Kinki criteria subclassifications have been proposed to better predict prognoses and determine appropriate treatment strategies for these patients. This study validated the prognostic significance within the Kinki criteria substages and analyzed the role of liver resection in patients with intermediate stage HCC. METHODS: Patients with intermediate stage HCC (n = 378) were retrospectively subclassified according to the Kinki criteria (B1, n = 123; B2, n = 225; and B3, n = 30). We analyzed the overall survival (OS) and treatment methods. RESULTS: The OS was significantly different between adjacent substages. Patients in substage B1 who underwent liver resection had a significantly better prognosis than those who did not, even after propensity score matching (PSM). Patients in substage B2 who underwent liver resection had a significantly better prognosis than those who did not; however, there was no difference after PSM. There was no difference in prognosis based on treatments among patients in substage B3. CONCLUSIONS: The Kinki criteria clearly stratify patients with intermediate stage HCC by prognosis. For substage B1 HCC patients, liver resection provides a better prognosis than other treatment modalities. In patients with substage B2 and B3, an alternative approach is required.

Cell competition controls differentiation in mouse embryos and stem cells.

Cell competition is a short-range intercellular communication, in which cells compare their fitness with that of their neighbors and eliminate the cells with relatively lower fitness. It is considered important for the formation and maintenance of healthy tissues; however, its exact role during development, especially in mammals, has been obscure. Recent studies in mouse embryonic epiblast and skin tissues revealed that cell differentiation in early embryos and stem cell proliferation tends to produce suboptimal cells, especially during early developmental stages. Cell competition occurs at multiple stages and via multiple mechanisms during development to ensure elimination of such low-quality cells. Thus, quality control via cell competition supports correct development by overcoming the heterogeneity produced during cell differentiation and stem cell proliferation.

Improvement of Learning and Memory in Senescence-Accelerated Mice by S-Allylcysteine in Mature Garlic Extract.

S-allylcysteine (SAC), a major thioallyl compound contained in mature garlic extract (MGE), is known to be a neuroactive compound. This study was designed to investigate the effects of SAC on primary cultured hippocampal neurons and cognitively impaired senescence-accelerated mice prone 10 (SAMP10). Treatment of these neurons with MGE or SAC significantly increased the total neurite length and number of dendrites. SAMP10 mice fed MGE or SAC showed a significant improvement in memory dysfunction in pharmacological behavioral analyses. The decrease of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, N-methyl-d-aspartate (NMDA) receptor, and phosphorylated α-calcium/calmodulin-dependent protein kinase II (CaMKII) in the hippocampal tissue of SAMP10 mice fed MGE or SAC was significantly suppressed, especially in the MGE-fed group. These findings suggest that SAC positively contributes to learning and memory formation, having a beneficial effect on brain function. In addition, multiple components (aside from SAC) contained in MGE could be useful for improving cognitive function by acting as neurotrophic factors.

Deletion of the Dishevelled family of genes disrupts anterior-posterior axis specification and selectively prevents mesoderm differentiation.

The Dishevelled proteins transduce both canonical Wnt/ß-catenin and non-canonical Wnt/planar cell polarity (PCP) signaling pathways to regulate many key developmental processes during embryogenesis. Here, we disrupt both canonical and non-canonical Wnt pathways by targeting the entire Dishevelled family of genes (Dvl1, Dvl2, and Dvl3) to investigate their functional roles in the early embryo. We identified several defects in anterior-posterior axis specification and mesoderm patterning in Dvl1+/-; Dvl2-/-; Dvl3-/- embryos. Homozygous deletions in all three Dvl genes (Dvl TKO) resulted in defects in distal visceral endoderm migration and a complete failure to induce mesoderm formation. To identify potential mechanisms that lead to the defects in the developmental processes preceding gastrulation, we generated Dvl TKO mouse embryonic stem cells (mESCs) and compared the transcriptional profile of these cells with wild-type (WT) mESCs during germ lineage differentiation into 3D embryoid bodies (EBs). While the Dvl TKO mESCs displayed similar morphology, self-renewal properties, and minor transcriptional variation from WT mESCs, we identified major transcriptional dysregulation in the Dvl TKO EBs during differentiation in a number of genes involved in anterior-posterior pattern specification, gastrulation induction, mesenchyme morphogenesis, and mesoderm-derived tissue development. The absence of the Dvls leads to specific down-regulation of BMP signaling genes. Furthermore, exogenous activation of canonical Wnt, BMP, and Nodal signaling all fail to rescue the mesodermal defects in the Dvl TKO EBs. Moreover, endoderm differentiation was promoted in the absence of mesoderm in the Dvl TKO EBs, while the suppression of ectoderm differentiation was delayed. Overall, we demonstrate that the Dvls are dispensable for maintaining self-renewal in mESCs but are critical during differentiation to regulate key developmental signaling pathways to promote proper axis specification and mesoderm formation.

Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug.

The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap-a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.

Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases.

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.

A Fragment of S38AA is a Novel Plasma Biomarker of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-ß peptide (Aß) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aß or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD.