Undifferentiated state induced by Rb inactivation associated with metabolic reprogramming and inflamming

The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Projec

For Vol. 72, No.1 pp17-22 Total Hip Arthroplasty for Patients with Residual Poliomyelitis at a Mean Eight Years of Follow-up

In the article by Sonekatsu M et al. entitled “Total Hip Arthroplasty for Patients with Residual Poliomyelitis at a Mean Eight Years of Follow-up”, which appeared in the February 2018 issue, Vol.72, No.1, pp17-22, following corrections should be listed. Editorial Office sincerely apologizes for making mistakes in the previous galley proof, therefore republish a corrected version

Total Hip Arthroplasty for Patients with Residual Poliomyelitis at a Mean Eight Years of Follow-up

In patients with poliomyelitis, degenerative arthritis of the hip may be encountered in the paralytic or normal contralateral limb because of leg length discrepancy, pelvic obliquity, or severe deformities of the affected hip. Although total hip arthroplasty (THA) is one of the most common orthopedic procedures, there are few reports of THA in adult patients with residual poliomyelitis. From March 2001 to January 2011, 5 patients with residual poliomyelitis (6 hips) underwent THA using uncemented implants at our hospital. We retrospectively evaluated the Japanese Orthopedic Association (JOA) hip rating score, complications, and radiographs. All five patients’ follow-up information was available: 4.5 years minimum, 8.4 years average, range 4.5-15 years. Surgery was done at the same side of the paralytic limb in 2 hips and contralateral to the paralytic limb in four hips. All patients had pain relief and improvement in function; JOA hip rating score improved significantly from the mean of 45 preoperatively to 78 at the last follow-up (p=0.0313). There was no loosening or osteolysis in this series, and no cases of dislocation, infection or nerve palsy. These findings can contribute to decisions regarding treatment for arthritic hips in adults with residual poliomyelitis

Twists in views on RB functions in cellular signaling, metabolism and stem cells

One-quarter of a century ago, identification of the human retinoblastoma gene (RB) loci proved Knudson\u27s \u27two-hit theory\u27 that tumor suppressor genes exist. Since then, numerous works delineated crucial roles for the RB protein (pRB)-E2F transcription factor complex in G1-S phase transition. In addition, discovering the relationship between pRB and tissue-specific transcription factors enabled a better understanding of how cell cycle exit and terminal differentiation are coupled. Recent works provoked many exciting twists in views on pRB functions during cancer initiation and progression beyond its previously well-appreciated roles. Various mitogenic and cytostatic cellular signals appeared to modulate pRB functions and thus affect a wide variety of effector molecules. In addition, genetic studies in mice as well as other creatures incessantly force us to revise our views on pRB functions. This review will focus particularly on the roles of pRB in regulating intracellular signaling, cell metabolism, chromatin function, stem cells and cancer stem cells. © 2012 Japanese Cancer Association

Clustering of Primordial Black Holes from QCD Axion Bubbles

We study the clustering of primordial black holes (PBHs) and axion miniclusters produced in the model proposed to explain the LIGO/Virgo events or the seeds of the supermassive black holes (SMBHs) in arXiv:2006.13137. It is found that this model predicts large isocurvature perturbations due to the clustering of PBHs and axion miniclusters, from which we obtain stringent constraints on the model parameters. Specifically, for the axion decay constant $f_a=10^{16}~\mathrm{GeV}$, which potentially accounts for the seeds of the SMBHs, the PBH fraction in dark matter should be $f_\mathrm{PBH}\lesssim7\times 10^{-10}$. Assuming that the mass of PBHs increases by more than a factor of $\mathcal{O}(10)$ due to accretion, this is consistent with the observed abundance of SMBHs. On the other hand, for $f_a=10^{17}~\mathrm{GeV}$ required to produce PBHs of masses detected in the LIGO/Virgo, the PBH fraction should be $f_\mathrm{PBH}\lesssim6\times 10^{-8}$, which may be too small to explain the LIGO/Virgo events, although there is a significant uncertainty in calculating the merger rate in the presence of clustering.Comment: 18 pages, 11 figure

Tumor-vascular interactions promote STING-driven inflammation in the tumor microenvironment

The recruitment of T cells following intratumoral administration of Stimulation of Interferon Genes (STING) agonists in the tumor microenvironment (TME) is a critical event in the STING-driven antitumor immune response, a pathway with great relevance in the context of cancer immunotherapy. We have previously demonstrated that LKB1 mutation is associated with suppression of tumor cell STING levels and reduced production of T-cell chemoattractants such as CXCL10 in KRAS-driven non-small cell lung cancer (NSCLC). Consistent with this, immunohistochemical staining of patient samples showed poor infiltration of CD3, CD4, and CD8 T cells into LKB1 negative versus LKB1 intact cancer epithelium, and instead, retention of T-cells in stroma. To examine how LKB1 alters immune cell recruitment in a STING-dependent manner, we used a 3-D microfluidic co-culture system to study interactions between vasculature and tumor spheroids derived from a KRAS/LKB1 mutated (KL) cell line with LKB1 reconstitution +/- STING deletion. To form the vasculature, we co-cultured tumor spheroids with fibroblasts and endothelial cells for 7 days, and identified changes in morphology, cytokine production, and gene expression that occur in co-culture. We first observed that co-culture induced synergistic production of multiple immune cell chemo-attractants such as CXCL10, CCL2, CCL5, and G-CSF. Interestingly, this more physiologic ex vivo tumor model of LKB1 reconstitution revealed particularly strong cooperative production of STING-dependent cytokines such as CXCL10 in the vasculature. Moreover, STING depletion in LKB1 reconstituted tumor cells did not significantly attenuate production of CXCL10 and other cytokines in co-culture, suggesting that tumor/vessel interaction may promote STING activation in the vasculature regardless of cancer cell-intrinsic STING function. Furthermore, although there was no appreciable response after treatment of KL cancer cells with cGAMP based STING agonists, treatment of isolated 3-D vascular networks with cGAMP enhanced vascular permeability and increased production of CXCL10 and CCL5, possibly contributing to defective chemokine gradients that retain T cells near the vasculature. Thus, developing these more complex models that incorporate the vasculature may elucidate important aspects of STING biology and may ultimately aid further development of effective immunotherapies targeting this signaling axi

Reduction of Postoperative Pain by Addition of Intravenous Acetaminophen after Total Hip Arthroplasty: A Retrospective Cohort Study

We evaluated the analgesic effects of multimodal pain control in which intravenous acetaminophen (IV APAP) was added to the standard protocol for Japanese patients who had undergone a total hip arthroplasty (THA). We performed a retrospective cohort study of 180 patients aged 66.4±10.5 years (30% male) who had undergone a THA (Oct. 2014 to Feb. 2015) at our hospital. The control patients were administered the standard analgesic protocol: flurbiprofen axetil as a continuous intravenous infusion and oral celecoxib (NAPAP; n=109). The patients in the new analgesic protocol group received IV APAP in addition to the standard analgesic protocol (APAP; n=71). The primary outcome was the maximum value of postoperative pain the patients reported on a numerical rating scale (NRS) during the first 24 h post-surgery. A univariate analysis and multivariate analyses adjusted for age, sex, the stage of hip osteoarthritis, preoperative pain, and surgical time showed that the maximum postoperative pain NRS scores during the first 24 h after surgery was significantly lower when the APAP protocol was used. The addition of IV APAP to the current standard multimodal analgesia protocol for Japanese patients who have undergone a THA may decrease the patients’ postoperative pain

Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation

金沢大学がん進展制御研究所The Retinoblastoma (RB) tumor suppressor regulates G1/S transition during cell cycle progression by modulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment-resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G1/S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling. © 2017 Japanese Cancer Association

Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling

金沢大学がん研究所The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19 Arf, Trp53 and p21Cdkn1a. In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19Arf, Trp53, p21Cdkn1a and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling. © 2011 Macmillan Publishers Limited All rights reserved

Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation

Oncogene-induced cellular senescence is well documented, but little is known about how infinite cell proliferation induced by loss of tumor suppressor genes is antagonized by cellular functions. Rb heterozygous mice generate Rb-deficient C cell adenomas that progress to adenocarcinomas following biallelic loss of N-ras. Here, we demonstrate that pRb inactivation induces aberrant expression of farnesyl diphosphate synthase, many prenyltransferases, and their upstream regulators sterol regulatory element-binding proteins (SREBPs) in an E2F-dependent manner, leading to enhanced isoprenylation and activation of N-Ras. Consequently, elevated N-Ras activity induces DNA damage response and p130-dependent cellular senescence in Rb-deficient cells. Furthermore, Rb heterozygous mice additionally lacking any of Ink4a, Arf, or Suv39h1 generated C cell adenocarcinomas, suggesting that cellular senescence antagonizes Rb-deficient carcinogenesis. © 2009 Elsevier Inc. All rights reserved