Prevalence and clinical outcomes of vitamin D deficiency among Japanese multiple myeloma patients: a single-center observational study.

PURPOSE: Vitamin D plays a crucial role in skeletal metabolism and holds significant importance in the pathophysiology of multiple myeloma (MM). This study aimed to determine the prevalence of vitamin D deficiency among Japanese MM patients and its correlation with clinical outcomes. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were assessed in 68 MM patients at a single institution in Japan, analyzing their association with clinical status, laboratory parameters including procollagen type 1 N-propeptide (P1NP) and tartrate-resistant acid phosphatase 5b (TRACP-5b), health-related quality of life (HR-QOL) scores, and overall survival. Additionally, patients with suboptimal 25(OH)D levels received cholecalciferol supplementation (1000 IU/day), and changes in laboratory parameters were monitored. RESULTS: The median 25(OH)D level was 22 ng/ml, with 32% and 51% of patients exhibiting vitamin D deficiency (< 20 ng/ml) and insufficiency (20-29 ng/ml), respectively. The 25(OH)D levels were unrelated to sex, age, MM stage, or bone lesions, but the vitamin D-deficient group showed a tendency towards lower HR-QOL scores. Among patients achieving complete remission, vitamin D supplementation increased P1NP, while TRACP-5b remained unchanged. Overall survivals from vitamin D measurement and from MM diagnosis were significantly worse in the vitamin D-deficient group compared to the vitamin D-insufficient/-sufficient group. CONCLUSION: The study identified a considerable number of Japanese MM patients with insufficient serum vitamin D levels, with one-third being deficient. Additionally, vitamin D deficiency predicted poor overall survival in Japanese MM patients. Further investigation is required to determine whether vitamin D supplementation can improve the frailty and survival of vitamin D-deficient MM patients.

Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes.

The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray crystallography. Mechanistic study demonstrated the crucial role of hydroxy(aryl)iodonium tosylate as a precatalyst, which is generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid in the presence of a catalytic amount of p-toluenesulfonic acid.

Synthesis of α-(aminoethyl)-α,ß-enones via alkyne aza-Prins cyclization and their synthetic application to pyrrolidines.

We developed a synthetic method for α-(aminoethyl)-α,ß-enones from aryl-substituted homopropargyl sulfonamides and aldehydes, representing the first synthesis of conjugated enones via alkyne aza-Prins cyclization. These products could be converted into pyrrolidines by a formal 5-endo-trig cyclization.

Convenient Synthesis of Benziodazolone: New Reagents for Direct Esterification of Alcohols and Amidation of Amines.

Hypervalent iodine heterocycles represent one of the important classes of hypervalent iodine reagents with many applications in organic synthesis. This paper reports a simple and convenient synthesis of benziodazolones by the reaction of readily available iodobenzamides with m-chloroperoxybenzoic acid in acetonitrile at room temperature. The structure of one of these new iodine heterocycles was confirmed by X-ray analysis. In combination with PPh3 and pyridine, these benziodazolones can smoothly react with alcohols or amines to produce the corresponding esters or amides of 3-chlorobenzoic acid, respectively. It was found that the novel benziodazolone reagent reacts more efficiently than the analogous benziodoxolone reagent in this esterification.

Prognostic impact of trisomy 21 in follicular lymphoma.

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial).

BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

Sulfonylimino Group Transfer Reaction Using Imino-λ³-iodanes with I2 as Catalyst Under Metal-free Conditions.

A new practical procedure of imination for sulfide has been developed. The treatment of (N-tosylimino)-phenyl-λ³-iodane, PhINTs, with various sulfides in the presence of a catalytic amount of I2 under metal-free conditions affords the corresponding N-tosylsulfilimine compounds with moderate to good yields. This facile transfer procedure of the sulfonylimino group can also be applied to triphenylphosphine to produce the respective iminotriphenylphosphoranes in high yields. According to the reaction mechanism studies, the process of imination from (N-tosylimino)-phenyl-λ³-iodane to sulfide under the conditions may involve radical steps within the reaction mechanism.

Iodonium Salts as Benzyne Precursors.

Reactions involving benzyne and aryne intermediates have found widespread application in organic synthesis. Various benzyne precursors and benzyne generating procedures are known. Recently, methods of benzyne generation from diaryliodonium salts and related hypervalent iodine compounds have received considerable attention. These methods are characterized by mild reaction conditions and applicability in a broad range of chemical transformations. The present minireview is focused on the preparation and reactivity of hypervalent iodine based benzyne precursors. Furthermore, recent developments in their synthetic application are discussed.

2-Picoline catalyst-triggered [2 + 2 + 2] cycloaddition-type reaction of acetylenedicarboxylates, aldehydes and alkenes.

2-Picoline efficiently catalyzes the formation of α,ß-enones from acetylenedicarboxylates and aldehydes in the presence of alkenes, thereby leading to pyrans in moderate to good yields with complete regioselectivities. This synthetic method of pyrans is represented as a first example of catalytic and direct [2 + 2 + 2] cycloaddition of three different components under the metal-free conditions.

Oxidative cycloaddition of hydroxamic acids with dienes or guaiacols mediated by iodine(III) reagents.

[Bis(trifluoroacetoxy)iodo]benzene (BTI) and (diacetoxyiodo)benzene (DIB) efficiently promote the formation of acylnitroso species from hydroxamic acids in the presence of various dienes to give the corresponding hetero-Diels-Alder (HDA) adducts in moderate to high yields. The present method could be applied to the HDA reactions of acylnitroso species with o-benzoquinones generated by the oxidative dearomatization of guaiacols.

Preparation, structure, and reactivity of bicyclic benziodazole: a new hypervalent iodine heterocycle.

A new bicyclic organohypervalent iodine heterocycle derivative of benziodazole was prepared by oxidation of 2-iodo-N,N'-diisopropylisophthalamide with m-chloroperoxybenzoic acid under mild conditions. Single crystal X-ray crystallography of this compound revealed a five-membered bis-heterocyclic structure with two covalent bonds between the iodine atom and the nitrogen atoms. This novel benziodazole is a very stable compound with good solubility in common organic solvents. This compound can be used as an efficient reagent for oxidatively assisted coupling of carboxylic acids with alcohols or amines to afford the corresponding esters or amides in moderate yields.

Identification of vitreous proteins in retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a disorder of blood vessels in the retina developed in premature infants and the leading cause of the blindness in children. Proteomic analysis was performed to identify vitreous proteins specific to patients with ROP. Vitreous humor samples were obtained from three patients with ROP and two patients with congenital cataract, the latter included as a control group. The vitreous samples were separated by 2D-PAGE and the proteins running as definitive spots were identified by MALDI-TOF MS spectrometry. We identified 13 and 6 proteins in the vitreous from ROP and cataract patients, respectively. Albumin, transferrin, pigment epithelium-derived factor (PEDF) and transthyretin were found in both patient groups. In the samples from ROP patients, PEDF and transthyretin levels were lower than in those from cataract patients, and retinol binding protein 3 and prostaglandin D synthase were not detected. Of the 13 proteins, 9 proteins including α-2-macroglobulin, ceruloplasmin, α-fetoprotein, vitamin D-binding protein, α-1-antitrypsin, α-1-ß-glycoprotein, hemopexin, apolipoprotein A-1 and A-lV were found in vitreous samples of only the ROP patients. PEDF has anti-angiogenic and neurotrophic functions. Whether PEDF is increased or decreased in diabetic retinopathy has been controversial but we observed lower PEDF in the ROP samples than in the controls. The proteins specific to or decreased in ROP, if confirmed in future studies, may provide clue to understanding its pathogenesis.

Pseudocyclic Arylbenziodoxaboroles: Efficient Benzyne Precursors Triggered by Water at Room Temperature.

New organohypervalent iodine compounds, arylbenziodoxaborole triflates, were prepared from 1-acetoxybenziodoxaboroles and arenes by treatment with trifluoromethanesulfonic acid under mild conditions. Single crystal X-ray crystallography of these compounds revealed a pseudocyclic structure with a short intramolecular interaction of 2.698 to 2.717 Šbetween oxygen and iodine in the benziodoxaborole ring. These new pseudocyclic aryliodonium salts readily generate aryne intermediates upon treatment with water at room temperature. The generated aryne intermediates react with various substrates to give the corresponding aryne adducts in moderate to good yields. Furthermore, the new benzyne precursors can also work as arylating reagents towards aromatic rings. The aryne intermediates generated from arylbenziodoxaborole triflates selectively react with tert-butyl phenol forming products of ortho arylation in moderate yields.

Preparation, Structure, and Reactivity of Pseudocyclic Benziodoxole Tosylates: New Hypervalent Iodine Oxidants and Electrophiles.

New pseudocyclic benziodoxole tosylates were prepared by the treatment of 1-hydroxybenziodoxolones with p-toluenesulfonic acid or via ligand transfer reaction between PhI(OH)OTs (Koser's reagent) and substituted 2-iodobenzoic acids under mild condition. Single crystal X-ray crystallography of these compounds revealed a pseudocyclic structure with a short intramolecular interaction of 2.362 Šbetween oxygen and iodine in the iodoxole ring. Pseudocyclic benziodoxole tosylates readily react with various organic substrates as electrophiles or oxidants to afford the corresponding iodonium salts or the products of oxidation. Furthermore, these compounds can be used as efficient recyclable hypervalent iodine reagents. The reduced form of a pseudocyclic benziodoxole tosylate, 2-iodobenzoic acid, can be efficiently recovered from the reaction mixture by a simple acid-base liquid-liquid biphasic procedure.

Single-Step Synthesis of Iodinated Oxazoles from N-Propargyl Amides Mediated by I2/Iodosylbenzene/Trimethylsilyl Trifluoromethanesulfonate Systems.

A combination of I2, iodosylbenzene, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) is effective for single-step synthesis of iodinated oxazoles from N-propargyl amides via the aromatization of the iodocyclized intermediates, which has difficulty proceeding through conventional iodocyclization methods. Compared to the former method consisting of the metal-catalyzed cyclization of N-propargyl amides followed by halogenation of alkylideneoxazolines, the present reaction provides a facile and metal-free procedure.

Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.

Barluenga's reagent with HBF4 as an efficient catalyst for alkyne-carbonyl metathesis of unactivated alkynes.

Barluenga's reagent (IPy2BF4, Py = pyridine) treated with HBF4 efficiently catalyzes the inter- and intramolecular alkyne-carbonyl metathesis of unactivated alkynes with aldehydes or ketones, most of which proceed at room temperature. This work represents the first catalytic application of the Barluenga's reagent.

The modified corneocyte surface area measurement as an index of epidermal barrier properties: inverse correlation with transepidermal water loss.

BACKGROUND: Corneocyte surface area (CSA) is as established parameter for skin barrier function in humans. Measurement of canine CSA has been previously reported but has not been validated. HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate the validity of CSA as a barrier function parameter in dogs. ANIMALS: Six clinically normal beagle dogs. METHODS: CSA was measured and compared with transepidermal water loss (TEWL) using sequential tape stripping of the stratum corneum as a model of acute barrier disruption. Then, CSA and TEWL were measured at four anatomical sites (groin, lower back, nasal bridge and pinna). The correlation between the two indices was also evaluated. RESULTS: From the results of sequential tape stripping, CSA values gradually decreased with increasing number of tape strippings. The CSA values were inversely correlated with the TEWL ones. The two indices at different sites were variable and were strongly correlated. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine CSA was demonstrated to be a useful parameter for the canine skin barrier function. The results from the anatomical sites imply that the cephalic sites (nasal bridge and pinna) were lower than others in skin barrier function.

Heparin cofactor II is degraded by heparan sulfate and dextran sulfate.

Heparan sulfate normally binds to heparin cofactor II and modulates the coagulation pathway by inhibiting thrombin. However, when human heparin cofactor II was incubated with heparan sulfate, heparin cofactor II became degraded. Other glycosaminoglycans were tested, including hyaluronic acid, chondroitin sulfates, dermatan sulfate, and heparin, but only dextran sulfate also degraded heparin cofactor II. Pretreatment of heparan sulfate with heparinase reduced its heparin cofactor II-degrading activity. Heparan sulfate and dextran sulfate diminished the thrombin inhibitory activity of heparin cofactor II. Other serpins, including antithrombin III and pigment epithelium-derived factor, were also degraded by heparan sulfate. This is the first evidence of acidic polysaccharides exhibiting protein-degrading activity without the aid of other proteins.

Saccharin-based µ-oxo imidoiodane: a readily available and highly reactive reagent for electrophilic amination.

Three new saccharin-based hypervalent iodine compounds were prepared by the reaction of saccharine with (diacetoxyiodo)arenes or acetoxybenziodoxole. Structures of these new imidoiodanes were established by X-ray crystallography. The saccharin-based µ-oxo-bridged imidoiodane readily reacts with silyl enol ethers under mild conditions to give the corresponding α-aminated carbonyl compounds in moderate yields.