Synthesis of a Cyclic Hexaamide Consisting of a Brominated m-Phenylene Repeating Unit.

Aiming to synthesize a cyclic hexaamide, 4-bromo-3-(isobutylamino)benzoic acid was subjected to self-condensation reactions in the presence of either dichlorotriphenylphosphorane in 1,1,2,2-tetrachloroethane or tetrachlorosilane in pyridine. However, instead of the targeted cyclic hexaamide, the cyclic triamide and the cyclic tetraamide were obtained. The cyclic hexaamide was successfully synthesized via the self-condensation of the dimer, which was synthesized in five steps from 4-bromo-3-(isobutylamino)benzoic acid. A thorough screening of the self-condensation conditions was performed to improve the yield of the target macrocycle. In addition, the linear hexamer was synthesized by stepwise deprotection and condensation, and its cyclization afforded the cyclic hexaamide in good yield.

[Discordant lymphoma of diffuse large B-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified in a human T-cell leukemia virus type-I carrier].

A 69-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL) negative for Epstein-Barr virus-encoded small nuclear RNA 1 (EBER-1) in October 2011, when he was also diagnosed as having a human T-cell leukemia virus type-I (HTLV-1) carrier. He achieved complete response after six courses of R-CHOP therapy. In February 2015, the patient had high fever and markedly elevated serum lactate dehydrogenase (LDH) level. Bone marrow examination revealed infiltration of CD4-positive T-cell malignancy. Based on the tentative diagnosis of adult T-cell leukemia/lymphoma, modified LSG15 therapy was initiated. His symptoms and serum LDH level quickly improved after the start of treatment. During the treatment, HTLV-1 proviral DNA integration was reported negative, allowing his final diagnosis to be peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Despite discontinuation of chemotherapy in the middle of the second course due to the patient's preference, complete remission was reached. He remains in clinical remission at 28 months after the treatment discontinuation. Discordant lymphoma of DLBCL and PTCL-NOS in HTLV-1 carrier has not been well characterized and will be discussed with a literature review.

Development of Helical Aromatic Amide Foldamers with a Diphenylacetylene Backbone.

We designed and synthesized aromatic polyamides with a diphenylacetylene backbone, α-DPA and ß-DPA, bearing (S)-α- and (S)-ß-methyl-substituted triethyleneglycol (TEG) side chains, respectively, and examined their conformations in solution. Both polymers exhibit strong, solvent polarity-dependent circular dichroism spectra, which indicated that they take helical conformations in low-polarity solvents. The spectra were mirror images, depending on the chiral position of the side chains. Thus, the polyamide α-DPA bearing (S)-α-methyl-substituted TEG groups takes a left-handed helical conformation, while the polyamide ß-DPA with (S)-ß-methyl-substituted TEG groups takes a right-handed helical conformation. The difference in the screw sense of α-DPA and ß-DPA would be caused by the steric interaction between the main chain and the side chain, as observed in poly(p-benzamide) possessing (S)-ß-methyl-substituted TEG side chains (ß-PA) because the large cavity of the helical structure of DPA would disturb the solvophobically induced helical folding. Detailed conformational analyses of the oligoamides 6-12 with ß-methyl-substituted TEG groups were conducted. Theoretical calculations indicated that the oligoamides with ß-methyl-substituted TEG groups exist in a helical conformation with a cavity of 7 Å in diameter. The 1H NMR spectra of the oligomers revealed interactions with small anions such as chloride and acetate anions and with pyridinium cations.

Phase II Study of Treatment for Newly Diagnosed Multiple Myeloma Patients Over 75 Years Old with Alternating Bortezomib/dexamethasone and Lenalidomide/dexamethasone: the MARBLE Trial.

Elderly multiple myeloma (MM) patients, who are generally ineligible for transplantation, have high risks of death and treatment discontinuation, and require a regimen incorporating novel agents that balance safety, tolerability, and efficacy. We evaluated alternating bortezomib-dexamethasone and lenalidomide-dexamethasone treatments administered over a 63-day cycle in transplant-ineligible elderly patients with newly diagnosed MM. Subcutaneous bortezomib 1.3 mg/m2 was administered weekly on Days 1, 8, 15, and 22; oral lenalidomide 15 mg daily on Days 36-56; and oral dexamethasone 20 mg on Days 1, 8, 15, 22, 36, 43, 50, and 57 for 6 cycles. The primary endpoint was the overall response rate.

[Occurrence of acquired factor V inhibitor during antibiotic therapy for a surgical wound infection].

Acquired factor V (FV) inhibitor is a rare disorder. Herein we report a case of an 82-year-old Japanese woman with FV inhibitor exhibiting a pseudo decline in the activities of the multiple coagulation factors. After rectal cancer surgery, she received antibiotic therapy for wound infection. As prothrombin and activated partial thromboplastin time was prolonged, heparin for atrial fibrillation was discontinued without improvement. Coagulation factor activity assays revealed deficiencies in II, V, VII, VIII, IX, X, XI, and XII factor activities; in particular, the FV activity was markedly decreased to <1%. The cross-mixing test findings revealed an inhibitor pattern, and multiple coagulation factor inhibitors were positive. The FV inhibitor level was high at 62 Bethesda U/ml. The patient exhibited no bleeding tendency with the prolonged wound infection without immunosuppressive therapy. The inhibitor disappeared four months after the onset.

First isolation and genetic characterization of pseudocowpox virus from cattle in Japan.

BACKGROUND: Pseudocowpox virus (PCPV) infects cattle worldwide with zoonotic potential but has not been isolated in Japan. Thus, the epidemiological status of PCPV infection in cattle is undetermined. RESULTS: In May 2016, a cattle in a farm in Yamaguchi Prefecture showed white vesicles and hyperemia in the mucosa under the tongue surface, but not on the teats and coronary cushions. A parapoxvirus was isolated from the oral lesion swab and was genetically characterized based on the full-length sequence of B2L gene encoding viral envelope. Phylogenetic analysis showed that the isolated virus was classified into PCPV. CONCLUSION: This case indicates its potential spread in Japan. This is the first report of isolation of PCPV in Japan.

Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease.

Graft-versus-host disease (GVHD) is a major risk factor for prolonged humoral immunodeficiency and vaccine unresponsiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the underlying mechanisms for this immunodeficiency are poorly understood. In this article, we describe previously overlooked impacts of GVHD on lymph node (LN) stromal cells involved in humoral immune responses. In major- and minor-mismatched mouse allo-HSCT models, recipients with CD8(+) T cell-mediated GVHD suffered severe and irreversible damage to LN structure. These mice were susceptible to pathogenic infection and failed to mount humoral immune responses despite the presence of peripheral T and B cells. These humoral immune defects were associated with the early loss of fibroblastic reticular cells, most notably the CD157(+) cell subset, as well as structural defects in high endothelial venules. The disruption to these LN stromal cells was dependent on alloantigens expressed by nonhematopoietic cells. Blockade of the Fas-FasL pathway prevented damage to CD157(+) fibroblastic reticular cells and ameliorated LN GVHD. However, blockade of CD62L- or CCR7-dependent migration of CD8(+) T cells to the LN was insufficient to prevent stromal cell injury. Overall, our results highlight GVHD-associated loss of functional stromal cells and LN GVHD as a possible explanation for the prolonged susceptibility to infectious disease that is experienced by allo-HSCT patients.

[Relapsed/refractory multiple myeloma with CD138 shedding and formation of extramedullary disease in the common bile duct region presenting as obstructive jaundice].

A 56-year-old man was diagnosed with immunoglobulin (Ig) A-κ multiple myeloma in July 2007. After three courses of vincristine, adriamycin, and dexamethasone (VAD) chemotherapy, autologous peripheral blood stem cell transplantation was performed and achieved a very good partial response. In February 2010, an increase in the M-protein concentration and plasmacytoma in the L3/4 lumbar vertebrae were observed, and radiation treatment was performed. This was followed by administrations of bortezomib, lenalidomide, and thalidomide, none of which achieved a good response. In November 2011, the patient presented with obstructive jaundice, and imaging tests revealed tumorous lesions in the lower bile duct region and bilateral kidneys. Plasmacytoma was diagnosed from biopsy of the right renal mass. Radiotherapy to the common bile duct tumor resulted in jaundice amelioration, but the patient died despite subsequent treatment efforts. Autopsy revealed multiple extramedullary lesions in the abdominal cavity and in the region around the common bile duct. CD138 shedding was observed in the myeloma cells. We include a discussion of the literature on CD138 shedding and 38 reports of obstructive jaundice associated with extramedullary disease.

Comparison of Impressions of COVID-19 Vaccinations Stratified by the Number of Vaccinations Among Japanese Healthcare Professional University Students.

OBJECTIVE: Coronavirus infectious disease, that emerged in 2019 (COVID-19) has been a major public health issue not only in Japan, but also worldwide, and the implementation of a proper vaccination strategy has been important. To promote vaccination, the present study compared impressions of COVID-19 vaccinations stratified by the number of vaccinations among healthcare professional university students in Okayama, Japan, and suggests better vaccination strategies. METHOD: A total of 212 Japanese healthcare professional university students were enrolled in this clinical qualitative study using the text mining method. A self-reported questionnaire, including questions such as "What do you think about COVID-19 vaccinations?" was performed. We also examined the number of vaccinations, sex, history of COVID-19 infection, and daily mask use. RESULTS: A total of 5,935 words were obtained and "Think" (169 times) was the most frequently used followed by "Inject" (108 times), "Inoculation" (97 times), "Vaccine" (83 times), "Corona" (66 times) and "Side effects" (49 times). Characteristic words were "Safety" in non-vaccinated subjects and "Side effects" and "Necessary" in vaccinated subjects. In addition, "Safety" in non-vaccinated men and "Frightening" in non-vaccinated women were characteristic and fundamental features. CONCLUSION: Impressions of COVID-19 vaccinations stratified by the number of vaccinations differed among healthcare professional university students. The provision of appropriate information on safety to non-vaccinated subjects and side effects to vaccinated subjects appears to be necessary. In addition, sex-specific information may be required for non-vaccinated subjects.

Cardioprotective Effects of Sodium-Glucose Cotransporter Subtype Inhibition on Ischemic and Pharmacological Preconditioning.

BACKGROUND: Sodium-glucose cotransporter (SGLT) 2 inhibitors partially inhibit SGLT1 expression; however, whether a clinical dose of SGLT2 inhibitor abrogates ischemic preconditioning (IPC) is unknown, and the pharmacological cardioprotective effect under SGLT1 inhibition has not been examined. In this study, we investigated whether a clinical dose of tofogliflozin abrogates IPC and whether pharmacological preconditioning with olprinone has cardioprotective effects under SGLT1 inhibition. METHODS: Male Wistar rats were divided into seven groups (seven rats per group) and subjected to the following treatments before inducing ischemia/reperfusion (I/R; 30 minutes of coronary artery occlusion followed by 120 minutes of reperfusion): saline infusion control treatment (Con); ischemic preconditioning (IPC); IPC after phlorizin infusion (IPC+Phl); IPC after low-dose tofogliflozin infusion (IPC+L-Tof); IPC after high-dose tofogliflozin infusion (IPC+H-Tof); olprinone infusion (Olp); and Olp infusion after phlorizin infusion (Olp+Phl). RESULTS: The infarct size was significantly decreased in the IPC group, but not in the IPC+Phl group. In contrast, the infarct size decreased in the IPC+L-Tof and IPC+H-Tof groups. Additionally, Olp reduced the infarct size, and the effect was preserved in Olp+Phl groups. Phosphorylated AMP-activated protein kinase (AMPK) expression was lower in the IPC+Phl group compared to that in the IPC group. CONCLUSION: The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Synthesis of 2,3-bis(halomethyl)quinoxaline derivatives and evaluation of their antibacterial and antifungal activities.

Quinoxaline derivatives having bis(fluoromethyl), bis(chloromethyl), or bis(iodomethyl) groups at the 2- and 3-positions, and various electron-donating/withdrawing substituents at the 6- and/or 7-positions, were synthesized. Their antibacterial and antifungal activities were evaluated by means of minimum inhibitory concentration assays. The relationships between the substituents and the antimicrobial activities of the quinoxaline derivatives indicate that the electrophilicity of the halomethyl units plays an important role in generating the antimicrobial activity.

[Rapid improvement of fluid retention with lenalidomide plus low-dose dexamethasone for POEMS syndrome relapsed after autologous peripheral blood stem cell transplantation].

We report a 53-year-old male with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome who relapsed after autologous peripheral stem cell transplantation (ASCT), but responded extremely well to lenalidomide (LEN) plus low dose dexamethasone (Ld) therapy. The patient had been diagnosed with POEMS syndrome in November 2006, and underwent ASCT in February 2007. In July 2011, he developed respiratory distress, generalized edema, and massive bilateral pleural effusion. Plasma vascular endothelial growth factor (VEGF) and M protein were increased, strongly indicating a relapse. Ld therapy was remarkably effective for these symptoms, resulting in complete remission with M-protein becoming undetectable by immunofixation. Since completing 11 courses of therapy with an every 4 weeks regimen, he has remained in clinical remission. The patient's activities of daily living have also markedly improved from total physical incapacity to being able to stand with slight assistance. LEN is associated with a lower incidence of peripheral neuropathy than other new drugs. Although LEN has occasionally been given to patients with POEMS syndrome in recent years, there are still few reports on its use for patients with recurrent disease after ASCT. Our successful management of this patient suggests that Ld therapy is not only relatively safe but also a promising option for POEMS syndrome relapsing after ASCT.

Refractory cardiac arrest caused by type I Kounis syndrome treated with adrenaline and nicorandil: A case report.

RATIONALE: Kounis syndrome is a rare but life-threatening anaphylactic reaction that can lead to acute coronary syndrome and cardiac arrest, and requires prompt diagnosis. Adrenaline, which is used to treat anaphylaxis, may cause coronary vasoconstriction and worsen ischemia, whereas coronary vasodilators may dilate systemic vessels and exacerbate hypotension. Delayed diagnosis of Kounis syndrome and inadequate therapeutic intervention may thus lead to a poor outcome. PATIENT CONCERNS: A 59-year-old man was treated for sepsis due to a liver abscess. Following administration of daptomycin, the patient developed severe anaphylactic shock leading to refractory cardiac arrest. Because conventional cardiopulmonary resuscitation was ineffective, extracorporeal cardiopulmonary resuscitation was considered as an alternative approach. DIAGNOSES: On bedside monitoring during cardiopulmonary resuscitation, unexpected ST-segment elevation was found on lead II electrocardiogram. Accordingly, the patient was clinically diagnosed with Kounis syndrome. INTERVENTIONS: Nicorandil (6 mg/h), a coronary vasodilator with minimal blood pressure effects, was administered along with high doses of vasopressors, including adrenaline 0.2 µg/kg/min. OUTCOMES: After the initiation of nicorandil administration, the patient achieved return of spontaneous circulation and did not require extracorporeal cardiopulmonary resuscitation. Based on the elevated serum tryptase level, normal creatine kinase-MB range, and lack of stenosis on coronary angiography, the patient was definitively diagnosed with type I (coronary vasospasm) Kounis syndrome. He was subsequently transferred to the referring hospital without neurological sequelae. LESSONS: If anaphylaxis leads to refractory shock and cardiac arrest, ischemic changes on the electrocardiogram should be investigated to identify underlying Kounis syndrome. In addition to adrenaline, coronary dilators are the definitive treatment. Nicorandil may be a useful treatment option because of its minimal effect on blood pressure.

Oxovanadium complexes with quinoline and pyridinone ligands: syntheses of the complexes and effect of alkyl chains on their apoptosis-inducing activity in leukemia cells.

Vanadium complexes with quinoline ligands (1b-g) and pyridinone ligands (2b-d) were synthesized, and the effect of the length and shape of alkyl chains on the antiproliferative activity toward U937 cells was studied. For the synthesis of the vanadium complexes, quinoline and pyridinone ligands were prepared and then treated with VOSO(4) or VO(acac)(2). The vanadyl(IV) complexes were characterized by IR, ESR, and UV-vis spectroscopy and elemental analyses. The antiproliferative activity of 1a-g toward U937 cells showed little dependence on the length and shape of the alkyl chain. In contrast, a good correlation was found between the IC(50) values and partition coefficients (logP) values of 2a-c. Among them, 2c showed the highest inhibitory activity, and its IC(50) value was smaller than that of cisplatin. The apoptosis-inducing ability of 2b and 2c was supported by annexin V-propidium iodide staining experiments and agarose gel electrophoresis analysis. Inhibitors of caspase-3, -8, and -9 did not affect the antiproliferative activity of 2c, indicating that the apoptosis induced by 2c was via a caspase-independent pathway.

Synthesis and antimicrobial activity of 2,3-bis(bromomethyl)quinoxaline derivatives.

We synthesized 12 derivatives of 2,3-bis(bromomethyl)quinoxaline with substituents at the 6- and/or 7-positions, and evaluated their activities against bacteria and fungi. Of the 12 compounds, nine (1a-h, 1j, and 1k) showed antibacterial activity. The derivative 1g, which bears a trifluoromethyl group at the 6-position, showed the highest activity against Gram-positive bacteria, while 1c, which has a fluoro-group at the 6-position, showed the widest antifungal activity spectrum. However, only the derivative with an ethyl ester substitution, 1k showed activity against Gram-negative bacteria.

Synthesis of oxovanadium complexes and their apoptosis-inducing activity in leukemia cells.

Vanadium complexes with different ligands were synthesized and evaluated for antiproliferative activity on U937 cells. The alkyl chain length of the ligands affected the antiproliferative activity, and two complexes-3b and 4-exhibited strong activities with IC(50) values of 6.02 and 3.90 µM respectively. Annexin V staining and DNA ladder formation indicated that these complexes induced apoptosis in U937 cells.