High mobility group box-1 (HMGB1), a representative damage associated-molecular pattern (DAMP), has been reported to be involved in many inflammatory diseases. Several drugs are thought to have ...potential to control the translocation and secretion of HMGB1, or to neutralize extracellular HMGB1 by binding to it. One of these drugs, anti-HMGB1 monoclonal antibody (mAb), is highly specific for HMGB1 and has been shown to be effective for the treatment of a wide range of CNS diseases when modeled in animals, including stroke, traumatic brain injury, Parkinson's disease, epilepsy and Alzheimer's disease. Thus, anti-HMGB1 mAb not only is useful for target validation but also has extensive potential for the treatment of the above-mentioned diseases. In this review, we summarize existing knowledge on the effects of anti-HMGB1 mAb on CNS and PNS diseases, the common features of translocation and secretion of HMGB1 and the functional roles of HMGB1 in these diseases. The existing literature suggests that anti-HMGB1 mAb therapy would be effective for a wide range of CNS and PNS diseases.
With a recent randomized prospective trial revealing that thermal ablative therapy as local tumor control improved overall survival (OS) in patients with unresectable colorectal cancer liver ...metastases (CRLM), thermal ablation continues to remain as an important treatment option in this patient population. Our aim of this article is to review the current role of the ablative therapy in the management of CRLM patients. Main indications for thermal ablation include (I) unresectable liver lesions; (II) in combination with hepatectomy; (III) in patients with significant medical comorbidities or poor performance status (PS); (IV) a small (<3 cm) solitary lesion, which would otherwise necessitate a major liver resection; and (V) patient preference. There are several approaches and modalities for ablative therapy, including open, percutaneous, and laparoscopic approaches, as well as radiofrequency ablation (RFA) and microwave ablation (MWA). Each approach and ablation modality have its own pros and cons. Percutaneous and laparoscopic approaches are preferred due to minimally invasive nature, yet laparoscopic approach has more benefits from thorough intraoperative ultrasound (US) exam as well as complete peritoneal staging with laparoscopy. Similarly, whereas high local tumor failure rate has been a major concern with RFA, MWA or microwave thermosphere ablation (MTA) have demonstrated significantly improved local tumor control due to homogenous tissue heating, ability to reach higher tissue temperatures, and less susceptible to the “heat-sink” effect. Although liver resection is the standard of care for CRLM, there have been some retrospective studies demonstrating similar oncological outcome between ablative therapy and surgical resection in very selected populations with small (<3 cm) solitary CRLM. Lastly, ablative therapy and liver resection should not be mutually exclusive, especially in the management of bilobar liver metastases. Concomitant ablative therapy with hepatectomy may spare the patients from having two-stage hepatectomy with less morbidity. The role of the thermal ablation will continue to evolve in patients with resectable and ablatable lesions owing to newly emerging technology, in addition to new systemic treatment options, including immunotherapy for metastatic colorectal cancer (CRC).
The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint ...plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy.
Long-term climate changes related with urbanization in Tokyo, Japan, and recent temperature and heavy rainfall distribution in the Tokyo metropolitan area are reviewed. A relatively high temperature ...increase in annual mean temperature at the rate of 3.0°C/century was detected in Tokyo for the period 1901–2015. Some observational evidence showed the existence of both thermal and mechanical effects of urbanization on recent heavy rainfall occurrences, and modeling studies also support precipitation enhancement. Urban influences were recognized in other climatological elements, such as number of fog days, relative humidity, and wind circulation.
Microwave thermosphere ablation is a new treatment modality that creates spherical ablation zones using a single antenna. This study aims to analyze local recurrence associated with this new ...treatment modality in patients with malignant liver tumors.
This is a prospective clinical study of patients who underwent microwave thermosphere ablation of malignant liver tumors between September 2014 and March 2017. Clinical, operative, and oncologic parameters were analyzed using Kaplan-Meier survival and Cox proportional hazards model.
One hundred patients underwent 301 ablations. Ablations were performed laparoscopically in 87 and open in 13 patients. Pathology included neuroendocrine liver metastasis (n = 115), colorectal liver metastasis (n = 100), hepatocellular cancer (n = 21), and other tumor types (n = 65). Ninety-day morbidity was 7% with one not procedure-related mortality. Median follow-up was 16 months with 65% of patients completing at least 12 months of follow-up. The rate of local tumor recurrence rate per lesion was 6.6% (20/301). Local tumor, new hepatic, and extrahepatic recurrences were detected in 15%, 40%, and 40% of patients, respectively. Local recurrence rate per pathology was 12% for both colorectal liver metastasis (12/100) and other metastatic tumors (8/65). No local recurrence was observed to date in the neuroendocrine liver metastasis and in the limited number of patients with hepatocellular cancers. Tumor size >3 cm and tumor type were independent predictors of local recurrence.
This is the first study to analyze local recurrence after microwave thermosphere ablation of malignant liver tumors. Short-term local tumor control rate compares favorably with that reported for radiofrequency and other microwave technologies in the literature.
High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity in the extracellular space. We previously demonstrated that intravenous injection of anti-HMGB1 monoclonal antibody ...(mAb) remarkably ameliorated brain infarction induced by middle cerebral artery occlusion in rats. In the present study, we focused on the protective effects of the mAb on the marked translocation of HMGB1 in the brain, the disruption of the blood-brain barrier (BBB), and the resultant brain edema.
Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with anti-HMGB1 mAb or control IgG intravenously. BBB permeability was measured by MRI. Ultrastructure of the BBB unit was observed by transmission electron microscope. The in vitro BBB system was used to study the direct effects of HMGB1 in BBB components.
HMGB1 was time-dependently translocated and released from neurons in the ischemic rat brain. The mAb reduced the edematous area on T2-weighted MRI. Transmission electron microscope observation revealed that the mAb strongly inhibited astrocyte end feet swelling, the end feet detachment from the basement membrane, and the opening of the tight junction between endothelial cells. In the in vitro reconstituted BBB system, recombinant HMGB1 increased the permeability of the BBB with morphological changes in endothelial cells and pericytes, which were inhibited by the mAb. Moreover, the anti-HMGB1 mAb facilitated the clearance of serum HMGB1.
These results indicated that the anti-HMGB1 mAb could be an effective therapy for brain ischemia by inhibiting the development of brain edema through the protection of the BBB and the efficient clearance of circulating HMGB1.
Microwave thermosphere ablation (MTA) is a new generation technology. The aim of this study was to compare the efficacy of MTA and radiofrequency ablation (RFA) in achieving local tumor control in ...patients with colorectal liver metastasis (CRLM).
This was a retrospective study of a prospective ablation database. Fifty-four patients with 155 CRLM lesions underwent RFA and 51 patients with 121 lesions underwent MTA. Patients were managed by a multidisciplinary team. Clinical and oncologic data were analyzed. Kaplan–Meier and Cox Proportional Hazards model were used for statistical analysis.
Demographics were similar between the two groups. Total ablation and operative times were significantly shorter in MTA group (19 vs. 37 mins, p < 0.001, 154 vs. 202 mins, p = 0.009). With a similar hospital stay (median 1), 90-day morbidity was similar (8 vs. 10%, p = 0.848), without mortality. Local recurrence (LR) rate per lesion was 20% in RFA and 10% in MTA group (p = 0.020). On Cox Proportion Hazards model, ablation modality and tumor size were independent predictors of LR.
This is the first study comparing the efficacy of RFA and MTA on CRLM. The results suggest that compared to RFA, MTA improves local tumor control, while significantly shortening operative time.
Glycyrrhizin (GL) is a major constituent of licorice root and has been suggested to inhibit the release of high mobility group box-1 (HMGB1), a protein considered representative of damage-associated ...molecular patterns. We found that GL bound HMGB1 but not RAGE with a moderate equilibrium dissociation constant value based on surface plasmon resonance analysis. This complex formation prevented HMGB1 from binding to RAGE in vitro. The effects of glycyrrhizin on traumatic brain injury (TBI) induced by fluid percussion were examined in rats or mice in the present study. GL was administered intravenously after TBI. Treatment of rats with GL dose-dependently suppressed the increase in BBB permeability and impairment of motor functions, in association with the inhibition of HMGB1 translocation in neurons in injured sites. The beneficial effects of GL on motor and cognitive functions persisted for 7 days after injury. The expression of TNF-α, IL-1β and IL-6 in injured sites was completely inhibited by GL treatment. In RAGE−/− mice, the effects of GL were not observed. These results suggested that GL may be a novel therapeutic agent for TBI through its interference with HMGB1 and RAGE interaction.
•Glycyrrhizin (GL) bound to HMGB1 directly with moderate affinity.•GL inhibited the binding between HMGB1 and its receptor RAGE.•GL inhibited traumatic brain injury by reducing HMGB1–RAGE interaction.•GL suppressed expression of inflammation-related molecules and brain edema.•GL may be a novel therapeutic agent for traumatic brain injury.
Recently, there has been increasing interest in new modalities such as therapeutic antibodies and gene therapy at a number of pharmaceutical companies. Moreover, in small-molecule drug discovery at ...such companies, efforts have focused on hard-to-drug targets such as inhibiting protein–protein interactions. Biomolecular NMR spectroscopy has been used in drug discovery in a variety of ways, such as for the reliable detection of binding and providing three-dimensional structural information for structure-based drug design. The advantages of using NMR spectroscopy have been known for decades (Jahnke in J Biomol NMR 39:87–90, (2007); Gossert and Jahnke in Prog Nucl Magn Reson Spectrosc 97:82–125, (2016)). For tackling hard-to-drug targets and increasing the success in discovering drug molecules, in-depth analysis of drug–target protein interactions performed by biophysical methods will be more and more essential. Here, we review the advantages of NMR spectroscopy as a key technology of biophysical methods and also discuss issues such as using cutting-edge NMR spectrometers and increasing the demand of utilizing conformational dynamics information for promoting small-molecule drug discovery.
While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less ...common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRNA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs.
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