Myeloid-derived suppressor cells (MDSCs) suppress anti-tumor immunity in tumor bearers, which leads to tumor progression. Immune checkpoint blockers (ICBs) demonstrated significant efficiency against various cancers; however, their success rate is limited to approximately 20–30% in patients with cancer. To address this limitation, predictive biomarkers and combination therapies are required. Since MDSCs are supposed to be crucial for the resistance to ICBs, targeting MDSCs could be a promising approach for cancer immunotherapy. Granulocyte colony-stimulating factor (G-CSF), widely used as prophylaxis and therapy for febrile neutropenia (FN), has been shown to significantly reduce its incidence. However, G-CSF has been reported to promote tumor progression caused by the enhancing the proliferation of MDSCs. We found that G-CSF enhances the immunosuppressive activity of MDSCs through the upregulation of γ-glutamyltransferase 1 (GGT1). GGT1, an enzyme hydrolyzing extracellular glutathione, is reported to be a marker for early-stage cancers and promote tumor progression. It is suggested that GGT1 increases glutamate levels through glutathione hydrolysis and that metabotropic glutamate receptor signaling enhances the immunosuppressive activity of MDSCs. Moreover, in FN mouse models, we observed that G-CSF promoted tumor progression, while the inhibition of GGT abolished. Together, the inhibition of GGT can mitigate the tumor-promoting effects of MDSCs without compromising the beneficial effect of G-CSF. These insights should lead to the safer and more effective cancer immunotherapy.

Molecularly targeted drugs currently used in breast cancer target the epidermal growth factor receptors, and are less effective when used against breast cancer subtypes with low levels of these receptors. There is therefore an urgent need to identify a new target molecule for such breast cancer subtypes. Vasoactive intestinal peptide (VIP) receptor 2 (VIPR2) is a G-protein-coupled receptor that binds to Gαs, Gαi, and Gαq proteins to regulate their downstream signaling. VIPR2 is known to be highly expressed in the suprachiasmatic nucleus of the brain, but is also expressed in many peripheral organs. VIPR2 expression has also been reported in thyroid cancer, gastric cancer, lung cancer, pancreatic adenocarcinoma, sarcoma, and neuroendocrine tumors, and VIPR2 mRNA expression and VIPR2 gene copy number are particularly elevated in breast cancer. We therefore investigated the involvement of VIPR2 in the proliferation and migration of breast cancer cells. We showed that VIP-VIPR2 is a novel molecular mechanism that controls cell migration by activating phosphatidylinositol-3 kinaseγ (PI3Kγ), promoting the production of phosphatidylinositol 3,4,5-triphosphate, and then regulating the formation and extension of pseudopodia. VIP-VIPR2 also regulated cyclin D1 levels through the cAMP/PKA/extracellular signal-regulated kinase and PI3K/AKT/Akt-glycogen synthase kinase-3β signaling pathways, thereby controlling cell proliferation by regulating the G1/S transition in the cell cycle. Treatment with a selective VIPR2 antagonist peptide KS-133 suppressed VIP-induced cell proliferation and migration. These results suggest that VIPR2 is a novel target molecule associated with breast cancer and that KS-133 is a potential molecular targeted drug for breast cancer.

Synovial sarcoma is a type of soft tissue sarcoma that predominantly occurs near the joints of the extremities in young adults. Its hallmark is a recurrent and pathogenic chromosomal translocation, t(X;18)(p11.2;q11.2), which results in the fusion of the SSX1 or SSX2 gene with SS18. The expressed SS18-SSX fusion protein induces abnormalities in the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, a chromatin remodeling complex. In this paper, we refer specifically to the human SWI/SNF complex as mSWI/SNF. Since 2020, significant progress has been made in elucidating the molecular mechanisms underlying the initial event in synovial sarcomagenesis, particularly in structural biology, thereby opening new possibilities for structure-based drug design (SBDD). SS18-SSX1 replaces the wild-type SS18, an essential subunit of mSWI/SNF, and in turn ejects SMARCB1, another core subunit of the complex. This aberrant mSWI/SNF complex (ssSWI/SNF) is then relocated to nucleosomes containing H2A K119Ub. H2A is one of the core histone proteins, and its 119th lysine residue is ubiquitinated to form H2A K119Ub. Chromatin domains harboring nucleosomes with this modification typically exhibit suppressed gene expression patterns. Furthermore, this region is occupied by polycomb complexes, but ssSWI/SNF competes with them, leading to gene activation, which constitutes the initial event in synovial sarcomagenesis. Given that SSX1 is normally expressed primarily in the testes, it is plausible that its ectopic expression leads to aberrant function within the chromatin remodeling complex. Ultimately, the C-terminal region of SSX1 was found to bind to the acidic patch within the nucleosome, and its structural details have been elucidated through cryo-electron microscopy.

Chemokines are a group of cytokines which are involved in the migration of immune cells as well as other cell types such as endothelial cells. These molecules normally regulate the homeostasis in our body’s immune system. Furthermore, it has been reported that chemokines mediate the onset and progression of various diseases including allergic diseases, autoimmune diseases, and cancers through the recruitment of immune cells to inflammatory sites. Glioblastoma is one of the primary brain tumors with a significantly poor prognosis. Similarly to other tumors, it has been observed that various immune cells infiltrate into the brain tumor tissues. However, the details of the mechanisms remain unclear. At present, cancer immunotherapy is vigorously researched, and is proved to be effective for many cancers. Unfortunately, the effectiveness of cancer immunotherapy has not yet been shown in glioblastoma. Chemokine is thought to be one of the important factors for cancer immunotherapy. Therefore, understanding the role of chemokines in glioblastoma is considered to be beneficial for the development of cancer immunotherapy. In this review, we overview the role of chemokines and these receptors in glioblastoma.

The global surge in antimicrobial resistance (AMR) highlights the critical need for the development of innovative therapies and the appropriate use of antimicrobial agents. Our research focused on preventing, managing, and mitigating the adverse effects of treatments for infection with methicillin-resistant Staphylococcus aureus. In this review, we present our investigations utilizing medical big data. The first study aimed to elucidate the relationship between renal outcome and survival following the onset of vancomycin-associated nephrotoxicity (VAN). An initial analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database revealed elevated mortality rates among patients with VAN compared with those without VAN, forming the basis for further investigation. A subsequent, more rigorous, retrospective analysis using electronic medical records confirmed that poor survival outcomes were significantly associated with non-recovery from VAN, particularly when progression to acute kidney injury of stage ≥2 occurred. Therefore, preventing progression to severe VAN is critical for enhancing survival outcomes. The second study investigated the relationship between statin use and daptomycin-related musculoskeletal adverse events. By employing a mixed-method approach combining meta-analysis with disproportionality analysis of the FAERS data, a significant association between statin therapy and daptomycin-related rhabdomyolysis was identified. This highlights the importance of cautious statin and daptomycin use, with careful consideration of potential safety risks. Each medical big-data database possesses unique characteristics that require careful consideration during analysis. The accurate interpretation of medical big data, coupled with its integration with complementary methodologies, will produce more robust and reliable research outcomes across diverse fields.

The global spread of antimicrobial resistance (AMR) is a threat to the international community, but few new antimicrobials are in the development stage and there are few options to treat AMR infections. In light of this situation, AMR has been continuously featured on the G7 agenda since 2015, and the 2023 G7 Hiroshima Leaders’ Communiqué also states that in recognition of the global and rapid spread of AMR, push and pull incentives will be explored and implemented. In addition, the World Health Assembly adopted the Global Action Plan on AMR in 2015, and Japan developed its first AMR action plan in 2016. An updated version has been released in 2023. It is hoped that the attractiveness of the antibiotic market will be improved, and the new antibiotic development will be revitalized by further expansion and enhancement of the pull incentive systems. Cefiderocol, a novel siderophore cephalosporin, demonstrates potent antibacterial activity against carbapenem-resistant Gram-negative bacteria, which are considered to be particularly high-priority pathogens by the World Health Organization (WHO) and other organizations. A partnership between the SHIONOGI, the Global Antibiotic Research and Development Partnership (GARDP) and the Clinton Health Access Initiative (CHAI) formed to improve access to cefiderocol in countries around the world, including low- and middle-income countries. In order to bring these efforts to fruition in the fight against AMR, it is important to have further understanding and cooperation from people around the world, regardless of country or field.

In recent years, many studies have been conducted on various diseases to evaluate clinical efficacy reflecting actual clinical conditions through comprehensive analysis using medical big data, which include various patient groups and factors in clinical practice. On the other hand, there are still very few research reports in the world related to the treatment of infectious diseases using medical big data. This is due to the fact that much medical big data lacks information on the causative organisms of infectious diseases and on determining the effectiveness of infectious disease treatment. In this paper, we introduce a research case study in which analysis on the effectiveness of infectious disease treatment was conducted using medical big data. In this study, we performed a retrospective analysis of two real databases with the aim of validating the usefulness of cefmetazole and flomoxef in urinary tract infections (UTI) in which broad-spectrum β-lactamase (ESBL)-producing bacteria are the primary initiating organisms. Third-generation cephalosporin-resistant E. coli and K. pneumoniae, including ESBL-producing strains, were similarly susceptible to flomoxef and cefmetazole. JMDC Claims data analysis showed that the median time of hospital stay duration was significantly shorter in the flomoxef group than in the cefmetazole group. Flomoxef exhibits effectiveness that is comparable to cefmetazole in treating UTI. When using currently available medical big data to conduct analyses related to infectious disease treatment, valuable analysis results may be obtained by understanding the characteristics of the database and collaborating with clinicians who are familiar with infectious disease treatment.

To advance our understanding of the neuronal mechanisms underpinning animal behavior, it is important to integrate traditional electrophysiological methodologies with cutting-edge technologies capable of providing detailed insights into the dynamics of neuromodulators. However, achievement of high spatial and temporal resolution in neuromodulator measurements has presented significant challenges, particularly in the context of real-time observations within freely behaving animals. Recent innovations, exemplified by the development of genetically encoded fluorescent indicator, commonly referred to as “GRAB sensors,” have addressed these limitations. These tools enable the real-time, high-precision quantification of neuromodulators, representing a transformative advancement in the field. Notably, GRAB sensors have been designed to target a broad spectrum of neuromodulators, including dopamine (DA), acetylcholine (ACh), noradrenaline/norepinephrine (NE), and neuropeptides, offering unparalleled specificity, sensitivity, and temporal resolution. This review provides an overview of the features and advantages of GRAB sensors, highlights their diverse applications, and discusses key considerations pertinent to their implementation in contemporary neuroscience research.

We are living in an era in which AI technology has become widely available and accessible to many people. The field of drug discovery is no exception, and many pharmaceutical companies have actually begun to utilize AI technology in drug discovery research. In the field of image analysis, which is our main business, AI technology is also advancing and being applied to drug discovery research. In this era of “democratization of AI”, what is the role of AI vendors including our company? What is needed for drug discovery researchers to use the technology correctly and appropriately in their research, and for more researchers to benefit from the technology than ever before? We would like to share with you what we have been doing so far and what we will do in the future for “true democratization of AI”, including examples of applications of image analysis AI technology to drug discovery research.

Upacicalcet sodium hydrate (upacicalcet) is a novel small-molecule calcium-sensing receptor (CaSR) modulator with an amino acid structure, developed in Japan as a derivative from research into taste enhancement. Upacicalcet specifically targets CaSR and is thought to inhibit parathyroid hormone (PTH) secretion by activating the receptor in the presence of extracellular calcium (Ca). In nonclinical studies, upacicalcet was evaluated for its pharmacological properties, binding characteristics, and effects on ectopic calcification, parathyroid hyperplasia, and bone disorders associated with secondary hyperparathyroidism (SHPT). The results supported its mechanisms of action, binding mode, and efficacy in suppressing disease progression. In clinical trials, upacicalcet demonstrated efficacy and safety in patients with SHPT undergoing hemodialysis, as assessed in domestic Phase I/II trial (AJ1001 trial), Phase II trial (AJ1002 trial), Phase III placebo-controlled trial (AJ1004 trial), and Phase III long-term administration trial (AJ1003 trial). Upacicalcet was approved in June 2021 for the treatment of secondary hyperparathyroidism (SHPT) in patients undergoing hemodialysis and was launched in August of the same year.