Synthesis, Structure, and Reactivity of Molybdenum- and Tungsten-Indane Complexes with Tris(pyrazolyl)borate Ligand.

The reaction of molybdenum complexes with a tris(pyrazolyl)borate ligand (Et4N[TpMo(CO)3] and Et4N[Tp*Mo(CO)3] (Tp = hydridotris(pyrazolyl)borate, Tp* = hydridotris(3,5-dimethylpyrazolyl)borate)) and InBr3 at a 1:1 molar ratio afforded molybdenum-indane complexes (Et4N[TpMo(CO)3(InBr3)] 1 and Et4N[Tp*Mo(CO)3(InBr3)] 2). In addition, tungsten-indane complexes, Et4N[TpW(CO)3(InBr3)] 3 and Et4N[Tp*W(CO)3(InBr3)] 4, were obtained by the reaction of corresponding tungsten complexes. Complex 4 reacted with H2O to form the hydrido complex Tp*W(CO)3H, in which the W-In bond was cleaved. On the other hand, 4 reacted with three equiv. of AgNO3 to form Et4N[Tp*W(CO)3{In(ONO2)}] 5, in which three substituents on the In were exchanged while retaining the W-In dative bond. Complexes 1-5 were fully characterized using NMR measurements and elemental analyses, and the structures of 1-5 and Et4N[Tp*W(CO)3] were determined via X-ray crystallography. These are the first examples of mononuclear molybdenum- and tungsten-indane complexes with Mo-In and W-In dative bonds.

Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study.

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.

Effect of prior olaparib maintenance therapy for platinum sensitive recurrent ovarian cancer on response to subsequent platinum-based chemotherapy.

AIM: Several years have passed since olaparib maintenance therapy was approved in patients with platinum sensitive recurrent ovarian cancer (PSROC). We speculated that the response to platinum-based chemotherapy (PBC) would be impaired at the time of recurrence after olaparib maintenance therapy. We conducted a noninterventional retrospective study to clarify this clinical question in a single institution. METHODS: We included all patients with PSROC who received olaparib after second or later line of PBC between April 18, 2018, and August 31, 2021. We evaluated the effect of olaparib maintenance therapy on PBC after progression. RESULTS: We identified 42 patients who received olaparib maintenance therapy after second or later line of PBC. Twenty-four patients relapsed after olaparib maintenance therapy, and 17 patients received PBC again. Four of 17 patients (complete response 2, partial response 2) responded to the PBC. The median progression-free survival was longer in patients with platinum-free interval ≥12 months than platinum-free interval of 6-12 months (9.7 vs 2.6 months, hazard ratio, 0.20: 95% confidence interval, 0.04-0.90; p = 0.04). CONCLUSIONS: In the patients with PSROC who experienced disease progression after olaparib maintenance therapy, especially in those with platinum-free interval of 6-12 months, the response to subsequent PBC was extremely poor. The efficiency of re-administration of PBC for PSROC patients with a short-term recurrence after olaparib treatment may need to be reconsidered.

Synthesis and Characterization of Phosphinecarboxamide and Phosphinecarbothioamide, and Their Complexation with Palladium(II) Complex.

Reactions of isocyanates/isothiocyanates with primary and secondary phosphines without solvent at room temperature afforded phosphinecarboxamide/phosphinecarbothioamide, respectively, in excellent yields. Furthermore, palladium complex Pd(COD)Cl2 was allowed to react with Ph2PC(O)NHPh (1a) to afford [Pd{Ph2PC(O)NHPh-κP}2Cl2] (3). On the other hand, the reaction of Pd(COD)Cl2 with 1 eq. of Ph2PC(S)NHPh (2a) afforded [PdCl2{Ph2PC(S)NHPh-κP,S}] (4). In the case of a 1:2 molar ratio, [PdCl{Ph2PC(S)NHPh-κP,S}{Ph2PC(S)NHPh-κP}]Cl (5) was formed. The newly obtained compounds were fully characterized using multielement NMR measurements and elemental analyses. In addition, the molecular structures of Ph2PC(O)NH(CH2)2Cl (1j), Ph2PC(S)NHPh(4-Cl) (2c), and 3-5 were determined using single-crystal X-ray diffraction.

Survival impact of adjuvant concurrent chemoradiotherapy after radical hysterectomy in FIGO stage IIIC1 cervical adenocarcinoma.

BACKGROUND: We evaluated the survival effect of adjuvant concurrent chemoradiotherapy after radical hysterectomy in patients with clinical pelvic node-positive cervical adenocarcinoma. METHODS: Patients with pelvic node-positive cervical adenocarcinoma diagnosed between 2000 and 2016 at our institution were identified. Survival was compared between patients who underwent radical hysterectomy alone and those who received concurrent chemoradiotherapy as an adjuvant treatment. Survival analysis using log-rank test and Cox proportional hazards model was performed. RESULTS: We identified 80 patients who underwent radical hysterectomy for clinical pelvic node-positive cervical adenocarcinoma; of these, four with pathological pelvic node-negative adenocarcinoma were excluded. Of the 76 patients, 27 underwent radical hysterectomy alone and 49 received radical hysterectomy followed by concurrent chemoradiotherapy. With a median follow-up of 53 months, the 5-year overall survival rate was 51.0% in patients who underwent radical hysterectomy alone versus 53.0% in patients who received additional concurrent chemoradiotherapy (log-rank p = 0.455). CONCLUSION: The addition of concurrent chemoradiotherapy after radical hysterectomy did not significantly improve survival among patients with pelvic node-positive cervical adenocarcinoma. More appropriate treatment strategies are needed to improve the survival outcomes of these patients.

Quality of life assessment of cell-free and concentrated ascites reinfusion therapy during initial treatment for advanced ovarian cancer: A prospective cohort study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) is applied to relieve symptoms in patients with malignant ascites. We performed a prospective cohort study to evaluate the efficacy and safety of CART performed on patients with advanced ovarian and peritoneal cancers with massive ascites during the initial treatment. METHODS: From April 2018 to July 2020, CART was performed during the initial treatment of 31 patients with advanced ovarian and peritoneal cancers with cancerous ascites. Patient characteristics and clinical information before and after CART were collected. We performed quality of life assessment using the Japanese version of the M.D. Anderson Symptom Inventory (MDASI-J) 24 h before and after CART. RESULTS: CART was performed 38 times in 24 patients before or during neoadjuvant chemotherapy and 11 times in 11 patients prior to surgery. Four patients underwent CART before primary surgery and before and/or during chemotherapy. Grade 1-2 fever was observed in 18 of 31 cases (58%), and all were controllable by nonsteroidal anti-inflammatory drugs. CART did not adversely affect the main treatment, chemotherapy, or surgery. CART significantly improved the MDASI-J symptom and interference scores within 24 h after the procedure. The symptom and interference scores decreased from 2.4 to 1.8 and from 4.8 to 3.0, respectively. CONCLUSIONS: CART can be safely performed and is useful for symptom relief and improvement of general condition prior to initial surgery and during initial chemotherapy in ovarian and peritoneal cancers. Performing CART at the time of initial treatment may facilitate initiation of the main treatment.

Allergen Stability and Immunological Reactivity during Co-dissolution and Incubation of House Dust Mite and Japanese Cedar Pollen SLIT-Tablets.

Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

The Effective Allergenic Reactivity of House Dust Mite Sublingual Immunotherapy Tablets Is Determined by Tablet Formulation.

House dust mite (HDM) sublingual immunotherapy (SLIT) in the form of SLIT-tablets is now an established treatment option for HDM allergy and HDM-induced allergic asthma. In SLIT-tablet immunotherapy allergen extracts are formulated as dry tablets and administered under the tongue where it must be solubilized in saliva in order to be able to interact with the immune system of the sublingual mucosa. Solubilization of the extract must occur within a short time span of about one minute after administration, determined by the sublingual holding time recommended by the manufacturer. Currently, two types of HDM SLIT-tablets are available. Both tablet types contain natural HDM extracts from two common HDM species as the active ingredient, but differ with regard to formulation as one tablet type is based on a freeze-dried tablet formulation while the other is based on a compressed formulation. HDM extracts contain a number of major and minor allergens, which in combination provide the allergenic activity that drives the immunological response and in turn the clinical efficacy of the tablets. Here, a biologically relevant human immunoglobulin E (IgE)-based assay is used to compare the ability of the two HDM SLIT-tablet types to deliver HDM allergenic reactivity from the dry tablet into soluble form. The experiments demonstrate that the freeze-dried formulation delivers HDM allergenic activity into solution faster and more efficiently than the compressed formulation.

Palladium-Borane Cooperation: Evidence for an Anionic Pathway and Its Application to Catalytic Hydro-/Deutero-dechlorination.

Metal-Lewis acid cooperation provides new opportunities in catalysis. In this work, we report a new type of palladium-borane cooperation involving anionic Pd0 species. The air-stable DPB palladium complex 1 (DPB=diphosphine-borane) was prepared and reacted with KH to give the Pd0 borohydride 2, the first monomeric anionic Pd0 species to be structurally characterized. The boron moiety acts as an acceptor towards Pd in 1 via Pd→B interaction, but as a donor in 2 thanks to B-H-Pd bridging. This enables the activation of C-Cl bonds and the system is amenable to catalysis, as demonstrated by the hydro-/deutero-dehalogenation of a variety of (hetero)aryl chlorides (20 examples, average yield 85 %).

Iridium-Catalyzed Aerobic Coupling of Salicylaldehydes with Alkynes: A Remarkable Switch of Oxacyclic Product.

The iridium(III)/copper(II)-catalyzed dehydrogenative coupling of salicylaldehydes with internal alkynes proceeds efficiently under atmospheric oxygen through aldehyde C-H bond cleavage and decarbonylation. A variety of benzofuran derivatives can be synthesized by the environmentally benign procedure. DFT calculations suggest that this unique transformation involves the facile deinsertion of CO in the key metallacycle intermediate, which is in marked contrast to the corresponding rhodium(III) catalysis that leads to CO-retentive chromone derivatives.

Selective Double Addition Reaction of an E‒H Bond (E = Si, B) to a C≡N Triple Bond of Organonitriles.

The catalytic double hydrometalation such as hydrosilylation and hydroborylation of organonitriles has attracted considerable attention because the obtained products are widely used in organic synthesis and it is thought to be one of the effective methods for reduction of organonitriles. However, the examples of these reactions are quite limited to date. This paper summarizes the development of selective double hydrosilylation, double hydroborylation, and dihydroborylsilylation of organonitriles, including their reaction mechanisms and the role of the metal species in the catalytic cycle.

Bioavailability of House Dust Mite Allergens in Sublingual Allergy Tablets Is Highly Dependent on the Formulation.

BACKGROUND: In sublingual immunotherapy (SLIT), the immune system is addressed by solubilized allergen that interacts with immunocompetent cells of the oral mucosa, the efficiency of which is governed by 2 main factors of SLIT allergen bioavailability: the allergen concentration and the mucosal contact time. Recently, 3 house dust mite (HDM) SLIT tablets were developed that differ with regard to allergen content, nominal strength (maintenance doses: 6 SQ-HDM/10,000 Japanese Allergen Units [JAU], 12 SQ-HDM/ 20,000 JAU, and 300 IR/57,000 JAU), and formulation (freeze-dried/compressed). Here, the importance of the SLIT tablet formulation for HDM major allergen bioavailability is examined. METHODS: The HDM major allergen content, tablet disintegration times, and allergen release kinetics were determined. Dissolution kinetics (allergen concentration vs. time) of Der f 1, Der p 1, and Der 2 were measured. Area under the curve (AUC) was used as a surrogate parameter for allergen bioavailability. RESULTS: The release of HDM major allergens from the freeze-dried tablets was complete after 30 s, while only partial release was achieved with the compressed tablets, even after prolonged dissolution. At 1 min, i.e., the recommended sublingual holding time for the freeze-dried tablets, the allergen bioavailability (AUC) of the compressed 300 IR/57,000 JAU tablet was 4.7-fold (Der f 1), 10.8-fold (Der p 1), and 23.6-fold (Der 2) lower than that of the freeze-dried 12 SQ-HDM/20,000 JAU tablet and similar to (Der f 1) and 5.3-fold (Der p 1) and 12.5-fold (Der 2) lower than that of the freeze-dried 6 SQ-HDM/10,000 JAU tablet. CONCLUSIONS: SLIT tablet allergen bioavailability depends highly on the tablet formulation. Only the fast-dissolving freeze-dried tablets provide maximal delivery of soluble allergens and achieve allergen concentrations that reflect the nominal tablet strengths within the recommended sublingual holding time.

Saturated Heavier Group 14 Compounds as σ -Electron-Acceptor (Z-Type) Ligands.

This review article describes the chemistry of transition-metal complexes containing heavier group 14 elements (Si, Ge, and Sn) as the σ-electron-acceptor (Z-type) ligands and discusses the characteristics of bonds between the transition metal and Z-type ligand. Moreover, we review the iridium hydride mediated cleavage of E-X bonds (E=Si, Ge; X=F, Cl), where the key intermediates are pentacoordinate silicon or germanium compounds bearing a dative M→E bond.

Selective Double Hydroboration and Dihydroborylsilylation of Organonitriles by an Iron-indium Cooperative Catalytic System.

Organonitriles (RC≡N) were selectively converted into the corresponding diborylamines (RCH2N(Bpin)2) in reactions with pinacolborane (pinBH) in the presence of a catalytic amount of the iron-indium complex [Fe(CH3CN)6][cis-Fe(CO)4(InCl3)2]. The catalytic reaction mechanism was tentatively proposed. In addition, this catalytic system was found to be applicable for the synthesis of borylsilylamine in high yield when organonitrile was treated with hydroborane and hydrosilane simultaneously.

Transition-Metal-Mediated Cleavage of Fluoro-Silanes under Mild Conditions.

Si-F bond cleavage of fluoro-silanes was achieved by transition-metal complexes under mild and neutral conditions. The Iridium-hydride complex [Ir(H)(CO)(PPh3 )3 ] was found to readily break the Si-F bond of the diphosphine- difluorosilane {(o-Ph2 P)C6 H4 }2 Si(F)2 to afford a silyl complex [{[o-(iPh2 P)C6 H4 ]2 (F)Si}Ir(CO)(PPh3 )] and HF. Density functional theory calculations disclose a reaction mechanism in which a hypervalent silicon species with a dative Ir→Si interaction plays a crucial role. The Ir→Si interaction changes the character of the H on the Ir from hydridic to protic, and makes the F on Si more anionic, leading to the formation of H(δ+) ⋅⋅⋅F(δ-) interaction. Then the Si-F and Ir-H bonds are readily broken to afford the silyl complex and HF through σ-bond metathesis. Furthermore, the analogous rhodium complex [Rh(H)(CO)(PPh3 )3 ] was found to promote the cleavage of the Si-F bond of the triphosphine-monofluorosilane {(o-Ph2 P)C6 H4 }3 Si(F) even at ambient temperature.

TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole: a theoretical and experimental study.

The mechanism of the TiCl4-promoted condensation of methyl acetoacetate, isobutyraldehyde, and indole was studied by a combination of theoretical and experimental techniques. The energy profile of plausible reaction paths was evaluated by DFT calculations, and various reaction intermediates were isolated or observed in solution by NMR spectroscopy. Theoretical and experimental results indicate that the reaction proceeds in three steps, all promoted by titanium: (1) formation of the enolate ion of methyl acetoacetate, (2) Knoevenagel condensation of the enolate ion and aldehyde, and (3) Michael addition of indole to the Knoevenagel adduct. The study sheds light on the role of titanium in the reaction, providing a mechanistic model for analogous reactions.

Factors affecting maternal serum magnesium levels during long-term magnesium sulfate tocolysis in singleton and twin pregnancy.

AIM: Our aim was to determine factors that affect maternal serum magnesium (Mg) levels, to help ensure the safety and efficacy of long-term magnesium sulfate (MgSO4 ) therapy for threatened preterm labor in singleton and twin pregnancies. MATERIAL AND METHODS: We retrospectively and arbitrarily studied 100 patients (singleton pregnancy, n = 65; twin pregnancy, n = 35) who received i.v. MgSO4 for >48 h for tocolysis of threatened preterm labor. We used multiple regression analysis to investigate the functional relations between the candidate factors and maternal serum Mg levels. RESULTS: MgSO4 was administered as a loading dose of 3 g for 1 h followed by a maintenance dose of 1.0-2.0 g/h. There were no maternal severe adverse events related to the elevated Mg levels in any of the subjects. The results of multiple regression analysis revealed that total dose of MgSO4 for 24 h before blood collection (g/day), total serum protein level (g/dL), serum total calcium level (mg/dL), serum creatinine level (mg/dL) and maternal bodyweight (kg) significantly affected maternal serum Mg levels in both singleton and twin pregnancies (all P-values were < 0.001). Gestational age (weeks) and period of MgSO4 administration (days) at blood collection had no significant effect in singleton or twin pregnancies. CONCLUSION: Our study statistically shows that dose of MgSO4 , total serum protein level, serum total calcium level, serum creatinine level and maternal bodyweight are key factors to achieving safe and effective long-term tocolysis with MgSO4 in not only singleton but also twin pregnancies.

Selective boryl silyl ether formation in the photoreaction of bisboryloxide/boroxine with hydrosilane catalyzed by a transition-metal carbonyl complex.

Selective B-O-Si bond formation was achieved in the reaction of bisboryloxide O(Bpin)2 (pin = (OCMe2)2)/boroxine (MeBO)3 system with tertiary silane R3SiH in the presence of stoichiometric water and a catalytic amount of [M](CO)5 ([M] = Mo(CO), W(CO), Fe) to give boryl silyl ethers. Moreover, this reaction can be applied to various hydrosilanes (disilyl compounds and secondary silanes) and hydrogermane. Some of the boryl silyl ethers thus formed were confirmed by X-ray analysis.