KEIO JOURNAL OF MEDICINE最新文献

Angiogenesis, the development of new blood vessels, is a fundamental physiological process. In addition, angiogenesis plays a key role in the pathogenesis of several disorders, including cancer and eye disorders such as diabetic retinopathy and age-related macular degeneration (AMD). However, identifying the regulators of angiogenesis proved challenging. Numerous factors that stimulated angiogenesis in various bioassays were identified, but their pathophysiological role remained unclear. In 1989, we reported the isolation and cloning of vascular endothelial growth factor (VEGF, VEGF-A) as an endothelial cell-specific mitogen and angiogenic factor. The tyrosine kinases Flt-1 (VEGFR-1) and KDR (VEGFR-2) were subsequently identified as VEGF receptors. Loss of a single vegfa allele results in defective vascularization and embryonic lethality in mice, emphasizing the essential role of VEGF in the development of blood vessels. Subsequently, we reported that anti-VEGF monoclonal antibodies block growth and neovascularization in tumor models. These findings paved the way for the clinical development of a humanized anti-VEGF antibody and other VEGF inhibitors for cancer therapy. To date, several VEGF inhibitors represent standard of care for colorectal cancer and other difficult to treat malignancies. VEGF is also implicated in intraocular neovascularization associated with retinal disorders as well as neovascular AMD. Our group developed a humanized anti-VEGF-A antibody fragment (ranibizumab) for the treatment of wet AMD. Ranibizumab not only maintained but also improved visual acuity and has been approved worldwide for the treatment of wet AMD and other neovascular disorders. Other VEGF inhibitors, including bevacizumab and aflibercept, have also resulted in significant clinical benefits. Today anti-VEGF drugs represent the most effective therapy for intraocular neovascularization. Current research addresses the need to reduce the frequency of intravitreal injections as well the identification of additional pro-angiogenic pathways that could result in improving therapeutic outcomes.

The endoplasmic reticulum (ER), where newly synthesized secretory and transmembrane proteins are folded and assembled, has the ability to discriminate folded proteins from unfolded proteins and controls the quality of synthesized proteins. Only correctly folded molecules are allowed to move along the secretory pathway, whereas unfolded proteins are retained in the ER.The ER contains a number of molecular chaperones and folding enzymes (ER chaperones hereafter), which assist productive folding of proteins, and therefore newly synthesized proteins usually gain correct tertiary and quaternary structures quite efficiently. Yet unfolded or misfolded proteins even after assistance of ER chaperones are retrotranslocated back to the cytosol, ubiquitinated and degraded by the proteasome. This disposal system is called ER-associated degradation (ERAD). Thus, the quality of proteins in the ER is ensured by two distinct mechanisms, productive folding and ERAD, which have opposite directions.Under a variety of conditions collectively termed ER stress, however, unfolded or misfolded proteins accumulate in the ER, which in turn activates ER stress response or Unfolded Protein Response (UPR). The UPR is mediated by transmembrane proteins in the ER, and three ER stress sensors/transducers, namely IRE1, PERK and ATF6, operates ubiquitously in mammals. Thanks to these signaling pathways, translation is generally attenuated to decrease the burden on the folding machinery; transcription of ER chaperones is induced to augment folding capacity; and transcription of components of ERAD machinery is induced to enhance degradation capacity, leading to maintenance of the homeostasis of the ER. If ER stress sustains, cells undergo to apoptosis.I will talk on the mechanism, evolution, and physiological importance of the UPR and ERAD as well as its involvement in development and progression of various diseases.

The management of adult spinal deformity (ASD) requires a personalized, multidisciplinary approach. Effective treatment hinges on thorough assessment using advanced imaging to understand the severity and impact of the spinal curvature. This paper underscores the importance of tailoring treatment plans to individual patient factors such as age, health, and psychological well-being, weighing both surgical and non-surgical options.Non-surgical treatments like pain management and physical therapy are preferred initially. If surgery is necessary, candidate selection and the choice of surgical technique are crucial. Minimally invasive procedures and advanced technologies like robotics enhance precision and reduce risks.Postoperative care and continuous monitoring are essential to assess the success of the intervention and manage any complications. This comprehensive strategy aims to improve overall functionality and quality of life, ensuring that treatment addresses both the physical deformity and its broader impacts. (Presented at the 2010th Meeting, May 20, 2024).

Constipation is a complicated condition. Chronic constipation is diagnosed when constipation occurs for more than 3 months. Chronic constipation is classified using patient symptoms and the pathophysiology. New therapeutic agents to treat chronic constipation have recently been approved in Japan. However, treatments for constipation that is refractory to traditional laxatives have been approved, an algorithm for the treatment of chronic constipation has not yet been developed. The accumulation of knowledge and data is necessary to develop a new algorithm.

We encountered a-27-year-old female patient who developed refractory severe headache and photophobia after the first dose of COVID-19 vaccine. Despite her prior history of migraine, we diagnosed COVID-19 vaccine-induced aseptic meningitis. Symptoms were significantly resolved after methylprednisolone therapy. On reviewing the literature, we could find only nine similar cases, with over half of them affecting women aged 20-40 years. Although uncommon, aseptic meningitis should be suspected in patients with persistent or delayed onset of headache following COVID-19 vaccination.

The number of patients with chronic kidney disease (CKD) is on the rise worldwide, and there is urgent need for the development of effective plans against the increasing incidence of CKD. Podocytes, glomerular epithelial cells, are an integral part of the primary filtration unit of the kidney and form a slit membrane as a barrier to prevent proteinuria. The role of podocytes in the pathogenesis and progression of CKD is now recognized. Podocyte function depends on a specialized morphology with the arranged foot processes, which is directly related to their function. Epigenetic changes responsible for the regulation of gene expression related to podocyte morphology have been shown to be important in the pathogenesis of CKD. Although epigenetic mechanisms include DNA methylation, histone modifications, and RNA-based regulation, we have focused on DNA methylation changes because they are more stable than other epigenetic modifications. This review summarizes recent literature about the role of altered DNA methylation in the kidney, especially in glomerular podocytes, focusing on transcription factors and DNA damage responses that are closely associated with the formation of DNA methylation changes.

Gain-of-function mutations had been believed to function as a single mutation in oncogenes, although some secondary mutations, such as EGFR T790M mutations, are frequently acquired in patients that are resistant to tyrosine kinase inhibitor treatment. Recently, we and other investigators have reported that multiple mutations (MMs) frequently occur in the same oncogene before any therapy. In a recent pan-cancer study, we identified 14 pan-cancer oncogenes (such as PIK3CA and EGFR) and 6 cancer type-specific oncogenes that are significantly affected by MMs. Of these, 9% of cases with at least one mutation have MMs that are cis-presenting on the same allele. Interestingly, MMs show distinct mutational patterns in various oncogenes relative to single mutations in terms of mutation type, position, and amino acid substitution. Specifically, functionally weak, uncommon mutations are overrepresented in MMs, which enhance oncogenic activity in combination. Here, we present an overview of the current understanding of oncogenic MMs in human cancers and provide insights into their underlying mechanisms and clinical implications.

The sensory and immune systems have been studied independently for a long time, whereas the interaction between the two has received little attention. We have carried out research to understand the interaction between the sensory and immune systems and have found that inflammation and bone destruction caused by fungal infection are suppressed by nociceptors. Furthermore, we have elucidated the molecular mechanism whereby fungal receptors are expressed on nociceptors and skin epithelium, how they cooperate to generate fungal pain, and how colitis and bone metabolism are regulated by mechanosensors expressed on the gut epithelium. Recently, we found that nociceptors prevent septic death by inhibiting microglia via nociceptor-derived hormones. This review summarizes our current state of knowledge on pain biology and outlines the mechanisms whereby pain and immunity interact. Our findings indicate that the sensory and immune systems share a variety of molecules and interact with each other to regulate our pathological and homeostatic conditions. This prompted us to advocate the interdisciplinary science named "senso-immunology," and this emerging field is expected to generate new ideas in both physiology and immunology, leading to the development of novel drugs to treat pain and inflammation.

A 75-year-old man underwent distal gastrectomy for advanced gastric cancer in September 2018. During the adjuvant chemotherapy, computed tomography (CT) revealed recurrence sites in the liver and para-aortic lymph nodes. Therefore, chemotherapy was initiated. After first-line (capecitabine with oxaliplatin) and second-line (paclitaxel with ramucirumab) treatments, nivolumab was used as third-line chemotherapy. This treatment showed a strong effect against the tumor. However, following an immune-related adverse effect (irAE) because of nivolumab, the therapy was halted. The irAE was diagnosed with central adrenal insufficiency that was controllable by oral intake of steroids. CPT-11 was started and showed a similarly strong effect to that observed for nivolumab. Eventually, the recurrent tumor lesions became too small to be detected by CT. We discontinued CPT-11 at the request of the patient. Even after discontinuation, no recurrent sites have been observed, allowing us to declare a case of clinical complete response (cCR). In conclusion, even if irAEs occur in a patient, continuing chemotherapy should be considered. However, if cCR is achieved, discontinuation of chemotherapy might be a strategic treatment option.

The standard method for sleep state classification is thresholding the amplitudes of electroencephalography (EEG) and electromyography (EMG) data, followed by manual correction by an expert. Although popular, this method has some shortcomings: (1) the time-consuming manual correction by human experts is sometimes a bottleneck hindering sleep studies, (2) EEG electrodes on the skull interfere with wide-field imaging of the cortical activity of a head-fixed mouse under a microscope, (3) invasive surgery to fix the electrodes on the thin mouse skull risks brain tissue injury, and (4) metal electrodes for EEG and EMG recording are difficult to apply to some experimental apparatus such as that for functional magnetic resonance imaging. To overcome these shortcomings, we propose a pupil dynamics-based vigilance state classification method for a head-fixed mouse using a long short-term memory (LSTM) model, a variant of a recurrent neural network, for multi-class labeling of NREM, REM, and WAKE states. For supervisory hypnography, EEG and EMG recording were performed on head-fixed mice. This setup was combined with left eye pupillometry using a USB camera and a markerless tracking toolbox, DeepLabCut. Our open-source LSTM model with feature inputs of pupil diameter, pupil location, pupil velocity, and eyelid opening for 10 s at a 10 Hz sampling rate achieved vigilance state estimation with a higher classification performance (macro F1 score, 0.77; accuracy, 86%) than a feed-forward neural network. Findings from a diverse range of pupillary dynamics implied possible subdivision of the vigilance states defined by EEG and EMG. Pupil dynamics-based hypnography can expand the scope of alternatives for sleep stage scoring of head-fixed mice.