Enhanced ALOX12 Gene Expression Predicts Therapeutic Susceptibility to 5-Azacytidine in Patients with Myelodysplastic Syndromes.

5-azacytidine (AZA), a representative DNA-demethylating drug, has been widely used to treat myelodysplastic syndromes (MDS). However, it remains unclear whether AZA's DNA demethylation of any specific gene is correlated with clinical responses to AZA. In this study, we investigated genes that could contribute to the development of evidence-based epigenetic therapeutics with AZA. A DNA microarray identified that AZA specifically upregulated the expression of 438 genes in AZA-sensitive MDS-L cells but not in AZA-resistant counterpart MDS-L/CDA cells. Of these 438 genes, the ALOX12 gene was hypermethylated in MDS-L cells but not in MDS-L/CDA cells. In addition, we further found that (1) the ALOX12 gene was hypermethylated in patients with MDS compared to healthy controls; (2) MDS classes with excess blasts showed a relatively lower expression of ALOX12 than other classes; (3) a lower expression of ALOX12 correlated with higher bone marrow blasts and a shorter survival in patients with MDS; and (4) an increased ALOX12 expression after AZA treatment was associated with a favorable response to AZA treatment. Taking these factors together, an enhanced expression of the ALOX12 gene may predict favorable therapeutic responses to AZA therapy in MDS.

Anticoagulation against portal vein thrombosis reduces mortality and liver cirrhosis-related complications: A propensity score-matched study.

AIM: Portal vein thrombosis (PVT) is one of the common complications of liver cirrhosis. Although anticoagulation contributes to thrombus resolution and is considered the first-choice treatment, its impact on patients' prognosis is still controversial. This study aimed to clarify the benefit of anticoagulation on mortality, liver function, and the incidence of liver cirrhosis-related complications in cirrhotic PVT patients. METHODS: We conducted a multicenter retrospective review in which we included 78 eligible patients with PVT out of 439. After propensity score matching, 21 cirrhotic PVT patients were included in each one of the untreated control and anticoagulation groups. RESULTS: Overall survival was significantly improved in the anticoagulation group compared with the control group (p = 0.041), along with PVT size reduction (53.3% vs. 108.2%, p = 0.009). At the time of CT follow-up, the anticoagulation group showed a lower ALBI score (p = 0.037) and its prevalence of massive ascites was significantly lower (p = 0.043) compared with the control group. The incidence of overt encephalopathy was also lower in the anticoagulation group (p = 0.041). The cumulative incidence of bleeding events did not differ significantly between the two groups. CONCLUSIONS: Anticoagulation improves the survival of patients with cirrhotic PVT. Preserved liver function and reduced risks of cirrhosis-related complications under the treatment may have contributed to a better prognosis. Given its efficacy and safety, anticoagulation is worth initiating in patients with PVT.

Bortezomib Increased Vascular Permeability by Decreasing Cell-Cell Junction Molecules in Human Pulmonary Microvascular Endothelial Cells.

Bortezomib (BTZ), a chemotherapeutic drug used to treat multiple myeloma, induces life-threatening side effects, including severe pulmonary toxicity. However, the mechanisms underlying these effects remain unclear. The objectives of this study were to (1) investigate whether BTZ influences vascular permeability and (2) clarify the effect of BTZ on the expression of molecules associated with cell-cell junctions using human pulmonary microvascular endothelial cells in vitro. Clinically relevant concentrations of BTZ induced limited cytotoxicity and increased the permeability of human pulmonary microvascular endothelial cell monolayers. BTZ decreased the protein expression of claudin-5, occludin, and VE-cadherin but not that of ZO-1 and ß-catenin. Additionally, BTZ decreased the mRNA expression of claudin-5, occludin, ZO-1, VE-cadherin, and ß-catenin. Our results suggest that BTZ increases the vascular permeability of the pulmonary microvascular endothelium by downregulating cell-cell junction molecules, particularly claudin-5, occludin, and VE-cadherin.

Inhibitory Effect of Pyra-Metho-Carnil on Cancer Spheroid Growth Through Decrease in Glycolysis-associated Molecules.

BACKGROUND/AIM: Pyra-Metho-Carnil (PMC) has been identified as a novel candidate compound for treating numerous malignancies; however, its mechanism of action remains unknown. In this study, we conducted RNA-sequencing (RNA-seq) analyses to elucidate the mechanism of PMC against human colorectal cancer cells harboring mutant KRAS (mtKRAS). MATERIALS AND METHODS: RNA-seq analyses of the HKe3-wild-type KRAS and HKe3-mtKRAS spheroids treated with DMSO or PMC for 6 days were performed. RESULTS: RNA-seq data suggested that PMC treatment suppresses the aerobic glycolysis pathway in HKe3-mtKRAS spheroids through the down-regulation of the HIF1 pathway. Indeed, treatment with PMC markedly suppresses the absorption of glucose by spheroids and the secretion of lactate from them. CONCLUSION: PMC suppresses growth of cancer spheroid through down-regulation of cancer-specific glucose metabolism.

Association of T cell infiltration and morphological change of thymus gland with the aggravation of pulmonary emphysema in testosterone deficiency.

Chronic obstructive pulmonary disease is an inflammatory lung disease characterized by chronic bronchitis and emphysema. Our previous study revealed that testosterone depletion induced T cell infiltration in the lungs and aggravated pulmonary emphysema in orchiectomized (ORX) mice exposed to porcine pancreatic elastase (PPE). However, the association between T cell infiltration and emphysema remains unclear. The aim of this study was to determine whether thymus and T cells are involved in the exacerbation of PPE-induced emphysema in ORX mice. The weight of thymus gland in ORX mice was significantly greater than that of sham mice. The pretreatment of anti-CD3 antibody suppressed PPE-induced thymic enlargement and T cell infiltration in the lungs in ORX mice, resulting in improved expansion of the alveolar diameter, a marker of emphysema exacerbation. These results suggest that increased thymic function due to testosterone deficiency and the associated increased pulmonary infiltration of T cells may trigger the development of emphysema.

Dynamic Changes of Behavioral Despair, HPA Axis Activity, and Hippocampal Neurogenesis in Male Rats Induced by Social Defeat Stress.

BACKGROUND: Psychosocial stress factors, such as threat and defeat, are major risk factors for the development of depression. The precise mechanisms underlying stress-induced depression are not clearly understood because the stress response in the brain varies in a stress-frequency-dependent manner. In the current research milieu on the pathogenesis of depression, the focus is on depression-like behavioral phenotype, hypothalamic-pituitary-adrenal (HPA) axis, and hippocampal neurogenesis. However, most studies have evaluated the symptomatic features of depression at certain time points after exposure to psychosocial stress. Here, we examined the frequency-dependent effects of psychosocial stress on depression-related features in rats. METHODS: In the present study, different frequencies (one, two, three, or four times) of psychosocial stress were applied to 19 male Sprague-Dawley rats using a resident/intruder paradigm. Subsequently, the rats were subjected to a stress reactivity test to evaluate HPA axis activity, following which assessments of immobility behavior in the forced swimming test (FST) and adult neurogenesis were conducted. RESULTS: One-time stressed rats showed a decrease in immobility behavior in the FST and the amount of doublecortin (DCX)-positive cells. Two-time stress caused hypoactivity of the HPA axis. In contrast, immobility behavior and HPA axis activity were increased after four-time stress exposure, but the number of DCX-positive cells was decreased. CONCLUSIONS: Our findings suggest that psychosocial stress produces a biphasic effect on the symptoms of depression in a stress-frequency-dependent manner, which could provide insights to facilitate further pathogenesis research on depression.

Impact of Concomitant Use of Azoles on Bortezomib-related Adverse Drug Reactions Using JADER.

BACKGROUND/AIM: Azoles are widely used for prophylaxis in patients with haematologic malignancies and are well known as selective cytochrome P450 isoenzyme 3A4 inhibitors. Although the interaction between bortezomib and azoles has been reported, most previous studies were case reports or small clinical studies. Hence, we conducted a pharmacoepidemiological study to elucidate the impact of azoles on bortezomib-related adverse reactions, using the Japanese adverse drug event report database (JADER). PATIENTS AND METHODS: We extracted 19,567 reports on patients prescribed bortezomib and/or azoles. We classified cases into three groups, namely bortezomib, bortezomib and azoles, and azoles groups. We estimated the odds ratios (OR) for the impact of concomitant azole use on five bortezomib-related adverse drug reactions (peripheral neuropathy, thrombocytopenia, neutropenia, leukopenia, and interstitial lung disease) using logistic regression. RESULTS: The OR for peripheral neuropathy in the 'bortezomib and azoles' group was higher than that in the bortezomib group [OR=2.02, 95% confidence interval (CI)=1.32-3.08]. The magnitude of the interaction was stronger with itraconazole than that with fluconazole (itraconazole, OR=3.22, 95% CI=1.78-5.70; fluconazole, OR=1.56, 95% CI=0.86-2.72). CONCLUSION: We found an association between concomitant administration of azoles with bortezomib and peripheral neuropathy. Azoles may enhance bortezomib-induced peripheral neuropathy based on their pharmacokinetic properties.

A case of refractory immune checkpoint inhibitor-induced colitis with Clostridioides difficile infection.

The clinical symptoms of an immune checkpoint inhibitor (ICI)-induced colitis are similar to those of ulcerative colitis. ICI-induced colitis, like ulcerative colitis, may be complicated by other colitis, such as Clostridioides difficile infection (CDI). A 72-year-old man was admitted because of watery and bloody stools 10 times a day after three courses of nivolumab (antibodies against programmed death 1) and ipilimumab (cytotoxic T-lymphocyte-associated antigen-4) for stage IV renal cell carcinoma. Colonoscopy revealed erythema and multiple erosions in the colon. Histopathological examination of colonic mucosa revealed diffuse inflammatory cell infiltration and apoptosis. The initial cytomegalovirus antigen test and C. difficile detection assay results were negative. Based on these findings, we diagnosed the patient with ICI-induced colitis and discontinued ICI therapy. The symptoms did not improve despite the administration of Prednisolone and infliximab. A repeat colonoscopy revealed a new appearance of pseudomembranes from the sigmoid colon to the rectum one month after the start of these treatments. At this point, the patient tested positive for C. difficile. With treatment with vancomycin for CDI, the abdominal symptoms gradually decreased. Nivolumab alone was cautiously restarted. However, no colitis recurrence and further tumor reduction were observed. Here, we report our experience of a case of refractory ICI-induced colitis complicated by CDI. ICI-induced colitis may be complicated by CDI and should be carefully treated with repeated CDI testing if refractory to treatment. We believe that our observation will provide helpful information for determining an appropriate treatment strategy for ICI-induced colitis.

Experience of disruption of capsule endoscopy after prolonged retention.

Capsule endoscopy is an effective tool for evaluating small bowel diseases. Capsule retention is a complication of capsule endoscopy, but capsule disruption after retention has not been thoroughly studied. Only a few cases of capsule disruption have been reported. We report a case of capsule disruption after prolonged retention. A 73-year-old woman underwent capsule endoscopy for the evaluation of anemia. One week later, capsule retention was observed on radiography. Capsule removal was advised, but she refused because she did not have any symptoms. After 20 months, computed tomography revealed disrupted capsule fragments. Capsule removal was strongly recommended, and the patient agreed. All disrupted capsule fragments were removed using double-balloon endoscopy without complications. Intestinal perforation had been prevented by removing the disrupted capsule before the battery fluid leaked into the intestinal tract. Capsule retention, documented by imaging, should be addressed by removing the retained capsule immediately before capsule disruption occurs.

Oncostatin M regulates hematopoietic stem cell (HSC) niches in the bone marrow to restrict HSC mobilization.

We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.

A refractory human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis patient with lymphoma-type adult T-cell leukemia/lymphoma: A case report and review of the literature.

RATIONALE: Adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) are caused by HTLV-1, but the coexistence of both disorders is rare. The estimated incidence is approximately 3%. PATIENT CONCERNS: A 54-year-old man was unable to stand up because of spastic paraparesis 1 month after the onset. He developed lymphadenopathy in the left supraclavicular fossa 5 months after the onset. The spastic paraplegia and sensory symptoms below the thoracic spinal cord level worsened. DIAGNOSES: Both blood and cerebrospinal fluid (CSF) tests were positive for anti-HTLV-1 antibodies. The patient was diagnosed with rapidly progressive HAM/TSP. He was also diagnosed with lymphoma-type ATL by the biopsy specimen of the lymph node. CSF examination at the time of symptom exacerbation showed abnormal lymphocytes, suggesting central infiltration of the ATL in the central nervous system. INTERVENTIONS: Methylprednisolone pulse therapy and oral prednisolone maintenance therapy were administered for rapidly progressive HAM/TSP. Intrathecal injection of methotrexate was administered for the suggested central infiltration of the ATL. OUTCOMES: Methylprednisolone pulse therapy and intrathecal injection of methotrexate did not improve the patient's exacerbated symptoms. Five months later, clumsiness and mild muscle weakness of the fingers appeared, and magnetic resonance imaging showed swelling of the cervical spinal cord. Clonality analysis showed monoclonal proliferation only in the DNA of a lymph node lesion, but not in the CSF and peripheral blood cells. LESSONS: This was a case of rapidly progressive HAM/TSP associated with lymphoma-type ATL that was refractory to steroids and chemotherapy. The pathogenesis was presumed to involve ATL cells in the brain and spinal cord because of the presence of abnormal lymphocytes in the CSF, but DNA analysis could not prove direct invasion. This case suggests that when we encounter cases with refractory HAM/TSP, it should be needed to suspect the presence of ATL in the background.

Effects of Aspergillus fumigatus Conidia on Apoptosis and Proliferation in an In Vitro Model of the Lung Microenvironment.

BACKGROUND/AIM: Aspergillus is often detected in respiratory samples from patients with chronic respiratory diseases, including pulmonary fibrosis, suggesting that it can easily colonize the airways. To determine the role of Aspergillus colonization in pulmonary fibrosis, we cultured human lung epithelial A549 cells or murine embryo fibroblast NIH/3T3 cells with Aspergillus conidia in 3D floating culture representing the microenvironment. MATERIALS AND METHODS: Cells were cultured in two-dimensional (2D) and three-dimensional floating (3DF) culture with heat-inactivated Aspergillus fumigatus (AF) 293 conidia at an effector-to-target cell ratio of 1:10 (early-phase model) and 1:100 (colonization model), and RNA-sequencing and Western blots (WB) were performed. RESULTS: AF293 conidia reduced A549 cell growth in 2D and 3DF cultures and induced apoptosis in A549 spheroids in 3DF culture. RNA-sequencing revealed the increased expression of genes associated with interferon-mediated antiviral responses including MX dymamin-like GTPase 1 (MX1). Interestingly, the decreased expression of genes associated with the cell cycle was observed with a high concentration of AF293 conidia. WB revealed that epithelial-mesenchymal transition was not involved. Notably, AF293 conidia increased NIH/3T3 growth only in 3DF culture without inducing an apoptotic reaction. RNA-sequencing revealed the increased expression of genes associated with interferon signalling, including MX2; however, the decreased expression of genes associated with the cell cycle was not observed. CONCLUSIONS: AF affects both apoptosis of epithelial cells and the growth of fibroblasts. A deeper understanding of the detailed mechanisms underlying Aspergillus-mediated signaling pathway in epithelial cells and fibroblasts will help us to understand the lung microenvironment.

Testosterone deficiency promotes the development of pulmonary emphysema in orchiectomized mice exposed to elastase.

Testosterone deficiency is commonly observed in male patients with chronic obstructive pulmonary disease (COPD), which is characterized by chronic inflammation of the airways and pulmonary emphysema. Although clinical trials have indicated that testosterone replacement therapy can improve respiratory function in patients with COPD, the role of testosterone in the pathogenesis of COPD remains unclear. The aim of this study was to explore the effect of testosterone deficiency on the development of pulmonary emphysema in orchiectomized (ORX) mice exposed to porcine pancreatic elastase (PPE). ORX mice developed more severe emphysematous changes 21 d after PPE inhalation than non-ORX mice. Testosterone propionate supplementation significantly reduced PPE-induced emphysematous changes in ORX mice. PPE exposure also increased the number of neutrophils and T cells in bronchoalveolar lavage fluid (BALF) of mice that had undergone ORX and sham surgery. T cell counts were significantly higher in the BALF of ORX mice than of sham mice. Testosterone supplementation reduced the infiltration of T cells into BALF and alleviated emphysematous changes in the lungs of ORX mice. Our findings suggest that testosterone, a male-specific hormone, may suppress the development of pulmonary emphysema through the regulation of T cell-mediated immunity.

Endoscopic Closure of an Acute Duodenal Perforation Occurring during Endoscopic Ultrasound Using Endoclips and Polyglycolic Acid Sheets with Fibrin Glue.

Acute duodenal perforation during endoscopic ultrasound (EUS) is a serious complication. The conventional endoscopic treatment for duodenal perforations such as endoscopic clipping is unsatisfactory; recently, the effectiveness of over-the-scope clipping (OTSC) has been reported. A 91-year-old woman was referred to our hospital with the chief complaint of jaundice. Contrast-enhanced computed tomography showed a 2-cm mass in the pancreatic head; we planned EUS-guided fine-needle aspiration. During exploration for a puncture route from the duodenal bulb using a linear echoendoscope under carbon dioxide insufflation, the duodenal lumen was suddenly filled with blood. A perforation <15 mm was identified in the superior duodenal horn. We attempted an endoscopic closure with multiple endoclips but could not completely close the perforation site. Strips of bioabsorbable polyglycolic acid (PGA) sheets were placed over the gaps between the endoclips with biopsy forceps and fixed in place with fibrin glue, completely covering the perforation site. Two days after the procedure, the perforation site had closed. Nine days later, endoscopic biliary stenting was performed. The patient was diagnosed with pancreatic cancer through bile cytology, and the optimal supportive care for her age was selected. Endoscopic tissue shielding with PGA sheets and fibrin glue is increasingly being reported for use during gastrointestinal endoscopic procedures. In this case, surgery was avoided due to successful endoscopic treatment using endoclips and PGA sheets with fibrin glue without OTSC. This method may be useful for repairing acute duodenal perforations during EUS and should therefore be known to pancreatobiliary endoscopists.

Bortezomib enhances G-CSF-induced hematopoietic stem cell mobilization by decreasing CXCL12 levels and increasing vascular permeability.

Bortezomib (BTZ) is known to enhance the mobilization of hematopoietic stem and progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF). However, the most effective time at which to administer BTZ to produce this enhancing effect remains debatable, and the precise mechanism underlying the effect of BTZ is poorly understood. We addressed these questions in this article by performing animal experiments. First, in agreement with previous studies, BTZ administration 12 hours before blood collection was most effective for HSPC mobilization; in contrast, BTZ administration 3 days before blood collection negatively affected HSPC harvesting. Next, in terms of the mechanism of action, G-CSF, but not BTZ, downregulated the expression of very late antigen-4 on HSPCs and vascular cell adhesion molecule-1 on bone marrow (BM) stromal cells; however, intriguingly, both G-CSF and BTZ downregulated CXCL12 chemokine expression in BM. Notably, BTZ treatment also increased BM vascular permeability. These results suggest that the pro-mobilization effect of BTZ could involve the dissociation of HSPCs from BM stromal cells triggered by G-CSF, vascular hyperpermeability elicited by BTZ, and downregulation of CXCL12 concomitantly induced by G-CSF and BTZ.

A case of cytomegalovirus esophagitis during topical steroid therapy for eosinophilic esophagitis.

Systemic immune deficiency is a major cause of cytomegalovirus (CMV) esophagitis. We report a case of CMV esophagitis during topical steroid therapy of eosinophilic esophagitis (EoE) in a non-immunodeficient patient. An 85-year-old man with dysphagia was on a 6-year regimen of oral budesonide (1200 mcg daily) for EoE. He underwent right upper lobectomy and postoperative radiotherapy 25 years ago for lung squamous cell carcinoma. Esophageal cicatricial stenosis due to EoE or previous radiation therapy persisted. Esophagogastroduodenoscopy revealed ulcerating mucosa with a thick white coat originating from the fixed stenotic lesion to the oral side. Histopathological examinations revealed CMV esophagitis. All signs of CMV esophagitis rapidly disappeared after reducing the budesonide dose and initiating anti-viral treatment with ganciclovir and valganciclovir for 12 and 2 days, respectively. The patient continued topical budesonide 400 mcg daily after anti-viral therapy. The clinical course was uneventful and without CMV esophagitis recurrence. This suggests that topical steroid therapy, particularly the local stasis of steroids at stenotic lesions, may induce CMV esophagitis. This is the first report of CMV esophagitis complicating the local steroid therapy of EoE with a stenotic lesion. When EoE patients' clinical symptoms worsen with topical steroid therapy, CMV esophagitis should be considered.

Continuous psychosocial stress stimulates BMP signaling in dorsal hippocampus concomitant with anxiety-like behavior associated with differential modulation of cell proliferation and neurogenesis.

Bone morphogenetic protein (BMP) signaling in the hippocampus regulates psychiatric behaviors and hippocampal neurogenesis in non-stress conditions; however, stress-induced changes in hippocampal BMP signaling have not yet been reported. Therefore, we sought to examine whether psychosocial stress, which induces psychiatric symptoms, affects hippocampal BMP signaling. A total of 32 male Sprague-Dawley rats were exposed to a psychosocial stress using a Resident/Intruder paradigm for ten consecutive days. Subsequently, rats were subjected to a battery of behavioral tests (novelty-suppressed feeding test, sucrose preference test, and forced swimming test) for the evaluation of adult neurogenesis and activity of BMP signaling in the dorsal and ventral hippocampus. Repeated social defeat promoted anxiety-like behaviors, but neither anhedonia nor behavioral despair. Socially defeated rats exhibited an increase in the number of Ki-67-positive cells, decrease in the number of doublecortin (DCX)-positive cells, and decrease only in the dorsal hippocampus of the ratio of DCX-positive to Ki-67-positive cells, a proxy for newly-born cell maturation speed and survival. In contrast, no differences were observed in the number of 5-Bromo-2'-deoxyuridine (BrdU)-positive cells, indicating survival of newly-born cells both in the dorsal and ventral hippocampus. Furthermore, psychosocial stress significantly increased the BMP-4 and phosphorylated Smad1/5/9 expression levels specifically in the dorsal hippocampus. Our findings suggest that repeated psychosocial stress activates BMP signaling and differently affects cell proliferation and neurogenesis exclusively in the dorsal hippocampus, potentially exacerbating anxiety-related symptoms. Targeting BMP signaling is a potential therapeutic strategy for psychiatric disorders.

Muscarinic M1 receptors stimulated by intracerebroventricular administration of McN-A-343 reduces the nerve injury-induced mechanical hypersensitivity via GABAB receptors rather than GABAA receptors in mice.

Cholinergic neurons play an important role in the higher functions of the brain, such as the memory, cognition, and nociception. However, the exact mechanism behind how the stimulation of all the muscarinic M1 receptors in the entire brain results in the alleviation of partial sciatic nerve ligation (PSNL)-induced mechanical hypersensitivity has not been investigated. Thus, we examined which subtype of GABA receptor was involved in the alleviation of PSNL-induce mechanical hypersensitivity produced by an intracerebroventricular administration of a muscarinic M1 receptor agonist, McN-A-343. Administering a GABAA receptor antagonist, bicuculline, resulted in no changes to the McN-A-343-induced anti-hypersensitivity in PSNL mice whereas a GABAB receptor antagonist, CGP35348, dose-dependently inhibited the anti-hypersensitivity. Furthermore, CGP35348 increased mechanical hypersensitivity in naïve mice, and the hypersensitivity was blocked by NMDA receptor antagonists, MK-801 and D-AP5. Additionally, muscarinic M1 receptors colocalized with GABAB1 receptors and an NMDA receptor subunit, GluN2A, in a large region of the brain. Consequently, these results suggest that the activation of muscarinic M1 receptors in the entire brain reduces nerve injury-induced mechanical hypersensitivity via the GABAB receptors, and the activation of the GABAB receptors regulates glutamatergic transmission via NMDA receptors.

A case of esophageal cancer with human immunodeficiency virus infection that progressed rapidly after neoadjuvant chemoradiotherapy.

While antiretroviral therapy has improved mortality in patients with human immunodeficiency virus (HIV) infections, deaths caused by non-acquired immunodeficiency syndrome-defining malignancies are increasing. A woman in her 70s with HIV infection who was receiving antiretroviral therapy presented with dysphagia. She was diagnosed with esophageal cancer (cT3N2M0, stage III). She received neoadjuvant chemotherapy (cisplatin and 5-fluorouracil) and radiotherapy. During treatment, we continued administering antiretroviral therapy and prophylaxis for opportunistic infections, with due attention to side effects and drug-drug interactions. No severe adverse events occurred. The primary lesion and metastatic lymph nodes decreased in size after treatment; however, 1 month later, her cancer spread to other organs; thus, surgery was canceled. Her general condition rapidly worsened. She eventually died of cancer cachexia and aspiration pneumonia. No previous reports have mentioned the treatment plan and management of esophageal cancer in HIV-positive patients. This report presents a case of esophageal cancer with HIV infection that progressed rapidly after neoadjuvant chemoradiotherapy.