Search

Intestinal bacteria can be classified into "beneficial bacteria" and "harmful bacteria." However, it is difficult to explain the mechanisms that make "beneficial bacteria" truly beneficial to human health. This issue can be addressed by focusing on hydrogen-producing bacteria in the intestines. Although it is widely known that molecular hydrogen can react with hydroxyl radicals, generated in the mitochondria, to protect cells from oxidative stress, the beneficial effects of hydrogen are not fully pervasive because it is not generally thought to be metabolized in vivo. In recent years, it has become clear that there is a close relationship between the amount of hydrogen produced by intestinal bacteria and various diseases, and this report discusses this relationship.

Like humans, cancer affects companion animals with similar genetic risks and incident rates. To improve treatment strategies for pet cancers, new research models are necessary. Patient-derived 3D organoid culture models are valuable and ensure the development of new effective therapies. In the previous study, we established a 3D organoid-derived 2.5D organoid culture model that recapitulated some characteristics of their parental 3D organoids. In the present study, we aimed to generate a 2.5D organoid culture model directly from cancer-diseased dogs and cats using special 2.5D media. The primary cultured cells in 2.5D media (direct 2.5D organoids) showed better attachment, growth, marker expression, and faster proliferation speed than those cultured in normal Dulbecco's Modified Eagle Medium media. The direct 2.5D organoids showed expression of each specific marker to their original cancer tissues and exhibited tumorigenesis in vivo. Moreover, the direct 2.5D organoids exhibited concentration-dependent responses to anti-cancer drugs, and different sensitivity profiles were shown among the strains. Our data suggest that the direct 2.5D organoid culture model might become a useful tool beyond 2D cell lines to study cancer biology in companion animals and could provide new platforms for screening the anti-cancer drugs.

Nonalcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease, with the increased prevalence of obesity, type 2 diabetes, and metabolic disorders in recent years. As the disease progresses, it leads to hepatic fibrosis, which may progress to hepatocellular carcinoma, but there is still no cure for severe hepatic fibrosis. Currently, in order to develop drugs for the treatment of NASH, the effects of candidate drugs are evaluated by a long-term administration to mice and rats that are fed a high-fat or methionine-deficient diet to reproduce the pathology of fatty liver and liver fibrosis. Since drug development using these experimental animals is time-consuming and costly, in vitro models that reproduce the pathology of NASH have recently been developing. In this review, we will outline the current issues in the diagnosis and treatment of NASH, and introduce our research for the discovery of early diagnostic markers and the development of new therapeutic agents using liver organoid cultures derived from mouse models of NASH.

Juzen-taiho-to, a traditional Chinese herbal medicine, is used for patients with anorexia and fatigue in human medicine. In our previous study, granulated Juzen-taiho-to improved vincristine-induced gastrointestinal adverse effects through increasing gastric motility in dogs. As the effect of Hozen-S, the sweet liquid form of Juzen-taiho-to, on dog gastric motility has not been investigated, we examined the effect of administration of Hozen-S on gastric motility. Furthermore, we assessed dog plasma ghrelin level to further elucidate the mechanism of the effect of Hozen-S on gastric contraction. Finally, we assessed the palatability of Hozen-S compared to granulated Juzen-taiho-to and its effect on body weight in dogs. Administration of Hozen-S significantly increased gastric motility, plasma ghrelin concentration, and body weight. A palatability evaluation revealed that the dogs preferred Hozen-S to granulated Juzen-taiho-to. In conclusion, Hozen-S administration to dogs promoted gastric motility by raising plasma ghrelin levels. Considering these functional and palatability data, Hozen-S may replace granulated type Juzen-taiho-to and become a prominent traditional Chinese veterinary medicament.

Despite the fact that we have reported on the dangers of the explosion of hydrogen gas inhalers, hydrogen gas inhalers with explosive hazards are, as a matter of fact, still being sold today. In this study, we investigated past reports of hydrogen gas inhaler explosion accidents to clarify the causes of these explosion incidents. As a result of this investigation, we found that the central cause was the leakage of hydrogen gas inside the hydrogen gas inhaler. Although it is said that the explosive concentration of hydrogen is between 10% and 75%, and that the gas does not explode above 75% due to the lack of oxygen, we confirmed through a series of ignition experiments that explosions can occur even in hydrogen gas inhalers that produce 100% hydrogen gas. Some manufacturers of such highly concentrated hydrogen gas inhalers claim that the high concentration and purity of hydrogen is safe and that there is no risk of explosion. We believe that manufacturing or selling such products that pose a risk of explosion or detonation is a violation of social justice. This paper presents ideas for selecting safe hydrogen gas inhalers based on a survey of past accident cases.

While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H2), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H2 has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H2 against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H2 as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.

Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (·OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.

Dog bladder cancer (BC) is mostly muscle-invasive (MI) with poor prognosis, and its pathogenesis is close to human MIBC. Three-dimensional (3D) organoid culture ensures novel knowledge on cancer diseases including BC. Recently, we have established dog BC organoids (BCO) using their urine samples. BCO recapitulated the epithelial structures, characteristics, and drug sensitivity of BC-diseased dogs. However, organoids from dog normal bladder epithelium are not established yet. Therefore, the present study aimed to establish dog normal bladder organoids (NBO) for further understanding the pathogenesis of dog BC and human MIBC. The established NBO underwent various analyzes including cell marker expressions, histopathological structures, cancer-related gene expression patterns, and drug sensitivity. NBO could be produced non-invasively with a continuous culturing and recapitulated the structures and characteristics of the dog's normal bladder mucosal tissues. Different drug sensitivities were observed in each NBO. The analysis of RNA sequencing revealed that several novel genes were changed in NBO compared with BCO. NBO showed a higher expression of p53 and E-cadherin, but a lower expression of MDM2 and Twist1 compared with BCO. These results suggest that NBO could be a promising experimental 3D model for studying the developmental mechanisms of dog BC and human MIBC.

Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.

Simple Summary In cases of cancer metastasis, some tumor cells circulate in blood (CTCs) and function as a seed for metastasis. These cells are important for detailed study of the molecular basis of metastasis. However, their few numbers and difficult isolation hinder its analysis. Apheresis, a process used to isolate a specific component of blood, can efficiently separate peripheral blood monocyte (PBMC), whose density is closely like that of CTCs. In the present study we used the dogs as a precious model of human’s cancers to check the safety and feasibility of apheresis and to separate PBMC and infused MCF7 cells using Spectra Optia apheresis machine (Terumo). The process was performed safely to capture PBMC and MCF7. The captured MCF7 cells were regrown up in vitro and characterized. In conclusion, Spectra Optia apheresis machine (Terumo) can be used safely to isolate CTCs from dogs blood with precautions to keep hemodynamic stability. Abstract In patients with solid tumors, circulating tumor cells (CTCs) spread in their blood and function as a seed for metastases. However, the study of CTCs has been limited by their rarity, low frequency, and heterogeneity. The efficient collection of CTCs will contribute to further research of metastatic cancers. Apheresis is a process in which the whole blood of an individual is passed through a machine that isolates a particular constituent and returns the remainder to the circulation. In the present study, we investigated the safety and feasibility of apheresis to separate peripheral blood monocytes (PBMCs), whose density is closely similar to that of CTCs, and to capture intravenously administered human breast cancer cells, MCF7s, from the dogs. No life-threatening events were observed in dogs during the apheresis process. The changes in the hemogram were transient and recovered gradually within a few days after apheresis. During apheresis, 50 mL of PBMCs could be collected from each dog. Notably, a thrombus was formed along the circuit wall during apheresis, which decreased the blood collection pressure. MCF7 cells were successfully captured by the apheresis machine. The captured cells were regrown in vitro and characterized compared with the original cells. In conclusion, apheresis could be safely performed in dogs to isolate CTCs with precautions to maintain hemodynamic stability.

A 45-year-old man who presented with dyspnea and chest tightness was found to have obstructive lung disease and eosinophilia of 10,300 eosinophils/μL. The differential diagnosis encompassed causes of primary eosinophilia and secondary eosinophilia associated with pulmonary disease, including asthma, environmental allergic reaction, eosinophilic granulomatosis with polyangiitis, allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, parasitic infections, tuberculosis, fungal infection, sarcoidosis, mastocytosis, drug reaction with eosinophilia and systemic symptoms, lymphoproliferative hypereosinophilic syndrome, and myeloproliferative hypereosinophilic syndrome. Infectious workup, fiberoptic bronchoscopy with biopsy, and tests for myeloproliferative mutations help differentiate among these causes. Identifying the underlying cause of eosinophilia is imperative in guiding treatment.

Attention to the health and wellness of postgraduate medical trainees has increased considerably in recent years, yet the scholarly literature consistently indicates that, in many instances, the medical and mental health care needs of this population remain unmet or only partially met. As a result, trainee health care often falls short of the current standards of the medical profession. Combined with the prevalence of burnout and other mental health conditions among trainees, inadequate health care for this patient population may result in significant negative consequences for trainees' health, safety, and performance.Here, the authors review the scholarly literature explicating the health care needs of postgraduate trainees. They explore the patient-centered medical home model as a potentially effective solution to address the unmet and partially met health care needs of trainees. The authors describe several practical interventions to improve access to care. These include care coordination and referral support, confidential care without perceived conflicts of interest in the training environment, co-location of medical and mental health care, and accommodations for schedule constraints. Finally, the authors explore the role of the medical home in developing and supporting broader institutional efforts to promote wellness.

Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.

BACKGROUND:A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown.PATIENTS AND METHODS:Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed.RESULTS:In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.CONCLUSION:mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC. BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown.PATIENTS AND METHODS: Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed.RESULTS: In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment.CONCLUSION: mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC.

503 Background: A significant minority of mRCC patients prematurely discontinue first-line (1L) VEGF-TT due to toxicity. Whether clinical outcomes differ in patients receiving second line (2L) TT based on reason for discontinuation of 1L are unknown. Methods: Patients from 15 International mRCC Database Consortium (IMDC) centers who started 2L TT were included and the reason for discontinuation of 1L collected. Treatment outcomes of 2L, including response, time to treatment failure (TTF) and overall survival (OS) were assessed. Results: 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT due to progression, 208 patients (19%) due to toxicity. 50 patients (4%) who discontinue due to other reasons were excluded. The reason for discontinuation of 1L did not differ by IMDC risk group at start of 1L VEGF-TT (p=0.54) or 2L therapy (p=0.52). Median time from 1L VEGF-TT initiation to start of 2L in patients who progressed or stopped prematurely due to toxicity was 9.8 and 7.9 months, respectively. Compared to patients who stopped 1L VEGF-TT due to progression, patients who stopped due to toxicity had longer drug free interval between 1L and 2L (1.4 vs. 0.7 months; p

430 Background: Third-line targeted therapy efficacy in metastatic renal cell carcinoma (mRCC) is not well characterized and many funding bodies do not provide reimbursement for it. Methods: The International mRCC Database Consortium (IMDC) consists of consecutive patient series from 25 cancer centers. It was queried for specific sequences of targeted therapy and third-line therapy. Kaplan Meier estimates were used for survival. Cox proportional hazards models were used to adjust hazard ratios for confounders. Patients that stopped second-line therapy were divided into two groups: those that went onto third-line therapy and those did not. Results: 4,050 patients were treated with first-line targeted therapy, of which 2,011 (49.6%) had second-line therapy and 879 (21.7%) had third-line targeted therapy. The most common third-line therapies were everolimus 25%, sorafenib 14%, sunitinib 13%, temsirolimus 11%, pazopanib 10%, and axitinib 6%. IMDC prognostic groups at third-line therapy initiation were 6% favorable risk, 67% intermediate risk, and 27% poor risk. Overall response rate for third-line therapy was 10.5% and 50.9% had stable disease in those patients that were evaluable. Median PFS was 5.1 months (95% CI, 4.5-5.7) and median OS from third-line therapy initiation was 12.0 months (95% CI, 10.7-12.9). Patients stopping second-line therapy that move on to third-line therapy vs. those that do not receive third line therapy have a median OS from stopping second-line therapy of 13.1 vs. 2.3 mons (p