Clinical characterization of patients with gBRCA1/2 mutation-positive unresectable pancreatic cancer: a multicenter prospective study.

BACKGROUND: Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan. METHODS & RESULTS: In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0-9.2). CONCLUSIONS: The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies.An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting.

Ir-Catalyzed Distal Branch-Selective Hydroarylation of Unactivated Internal Alkenes with Benzanilides via C-H Activation along with Consecutive Isomerization.

We herein report a synergistic strategy of C-H activation and consecutive isomerization catalyzed by an Ir catalyst to selectively obtain branched isomers as C-H alkylated products of benzanilide derivatives. A well-tuned ligand and a directing group are crucial to achieve this selectivity. The scope of this reaction is demonstrated by the use of a variety of substituents and complex molecules.

Sulfide-Directed Ir-Catalyzed Vinylic sp2 and Benzylic sp3 †C-H Activation for the Construction of Sulfur-Containing Medium-Ring System.

Ir-catalyzed transformations initiated by sulfur-directed vinylic sp2 and benzylic sp3  C-H activation are disclosed that achieve the construction of sulfur-containing seven- and eight-membered systems. Allyl 2-alkynylphenyl sulfides were transformed into dihydrobenzothiepines in 30-95 % yield, and 2-alkynylaryl 2-tolyl sulfides were converted into dibenzo[b,f]thiepines in 57-95 % yield along with double bond isomerization. In both reactions, the combination of Ir catalyst and sulfide moiety was a key to the facile cyclization.

Synthesis of Dithia[5]helicenes and Enantioselective Synthesis of Helically Chiral Thia[6]helicenes via Rh-Catalyzed Intramolecular [2 + 2 + 2] Cycloaddition of Triynes.

Dithia[5]helicenes and helically chiral thia[6]helicenes were synthesized in high yields via a cationic Rh-catalyzed intramolecular [2 + 2 + 2] cycloaddition of triynes bearing sulfur-containing 1,6-diynes. Thia[6]helicene could be obtained with a high enantiomeric excess of P-isomers by using (S)-SEGPHOS as a chiral ligand. This protocol is the first example of the synthesis of thiahelicenes via [2 + 2 + 2] cycloaddition and can also be used for the asymmetric construction of an aza[6]helical skeleton.

Experimental and Theoretical Evidence for Relativistic Catalytic Activity in C-H Activation of N-Phenylbenzamide Using a Cationic Iridium Complex.

This study elucidates that relativistic effect plays a key role in catalytic C-H activation using a cationic Ir complex. Experiments show that the cationic Ir(I)-diphosphine catalyst can be used for the deuterium substitution of N-phenylbenzamide, whereas a cationic Rh(I)-diphosphine catalyst is scarcely effective. Density functional theory calculations, including the relativistic effect, demonstrate a large difference in the reaction energy diagrams for the C-H activation of N-phenylbenzamide between the cationic Ir and Rh catalysts. In particular, the relatively low reaction barrier and considerably stabilized product obtained for the Ir catalysts are rationalized by strong Ir-C and Ir-H interactions, which originate from the relativistic self-consistent d-orbital expansion of Ir.

Development of a Flexible MEMS Sensor for Subsonic Flow.

Detection and control of flow separation is a key to improving the efficiency of fluid machinery. In this study, we developed a flexible MEMS (microelectromechanical systems) sensor for measuring the wall shear stress and flow angle in subsonic airflow. The developed sensor is made of a flexible polyimide film and a microheater surrounded by three temperature sensor pairs. The sensor measures the wall shear stress from the heater output and the flow angle from the temperature gradient around the heater. The geometry and design of the heater and temperature sensors were determined based on numerical simulations. To evaluate the validity of the sensor, we conducted an experiment to measure the wall shear stress and the flow angle in a wind tunnel in different velocities ranging from 30 m/s to 170 m/s, equivalent to Mach numbers from 0.1 to 0.5. The heater output was proportional to one-third power of the wall shear stress. Additionally, the bridge output correlating the temperature difference between two opposing temperature sensors showed sinusoidal variation depending on the flow angle. Consequently, we have clarified that the developed sensor can measure both the wall shear stress and flow direction in subsonic flow.

Guidelines for cadaver dissection in education and research of clinical medicine (The Japan Surgical Society and The Japanese Association of Anatomists).

This article translates the guidelines for cadaver surgical training (CST) published in 2012 by Japan Surgical Society (JSS) and Japanese Association of Anatomists from Japanese to English. These guidelines are based on Japanese laws and enable the usage of donated cadavers for CST and clinical research. The following are the conditions to implement the activities outlined in the guidelines. The aim is to improve medicine and to contribute to social welfare. Activities should only be carried out at medical or dental universities under the centralized control by the department of anatomy under the regulation of Japanese law. Upon the usage of cadavers, registered donors must provide a written informed-consent for their body to be used for CST and other activities of clinical medicine. Commercial use of cadavers and profit-based CST is strongly prohibited. Moreover, all the cadaver-related activities except for the commercial-based ones require the approval of the University's Institutional Review Board (IRB) before implementation. The expert committee organized at each university for the implementation of CST should summarize the implementation of the program and report the details of the training program, operating costs, and conflicts of interest to the CST Promotion Committee of JSS.

Guidelines for cadaver dissection in education and research of clinical medicine (The Japan Surgical Society and The Japanese Association of Anatomists).

This article translates the guidelines for cadaver surgical training (CST) published in 2012 by Japan Surgical Society (JSS) and Japanese Association of Anatomists from Japanese to English. These guidelines are based on Japanese laws and enable the usage of donated cadavers for CST and clinical research. The following are the conditions to implement the activities outlined in the guidelines. The aim is to improve medicine and to contribute to social welfare. Activities should only be carried out at medical or dental universities under the centralized control by the department of anatomy under the regulation of Japanese law. Upon the usage of cadavers, registered donors must provide a written informed-consent for their body to be used for CST and other activities of clinical medicine. Commercial use of cadavers and profit-based CST is strongly prohibited. Moreover, all the cadaver-related activities except for the commercial-based ones require the approval of the University's Institutional Review Board (IRB) before implementation. The expert committee organized at each university for the implementation of CST should summarize the implementation of the program and report the details of the training program, operating costs, and conflicts of interest to the CST Promotion Committee of JSS.

Ir-Catalyzed Remote Functionalization by the Combination of Deconjugative Chain-Walking and C-H Activation Using a Transient Directing Group.

An Ir-catalyzed reaction of N-benzylideneanilines with functionalized alkenes such as α,ß-unsaturated esters gave ortho-substituted benzaldehyde derivatives with a functional group at the remote position after acidic treatment. The present transformation involves deconjugative long-range isomerization (chain-walking) up to 11 times and C-H activation using an imino group as a transient directing group.

Ir-Catalyzed Enantioselective Formal C-H Conjugate Addition of Pyrrole and Indoles to α,ß-Unsaturated Carbonyl Compounds.

The chiral Ir(I)-catalyzed intermolecular reaction of N-carbamoylpyrrole and indole derivatives with α,ß-unsaturated carbonyl compounds such as crotonates proceeded with high enantioselectivity. The obtained chirally functionalized pyrroles and indoles are formal C-H conjugate adducts. The reaction mechanism was studied by deuterium labeling experiments.

Enantioselective Cross-Coupling of Electron-Deficient Alkenes via Ir-Catalyzed Vinylic sp2 C-H Alkylation.

A chiral Ir-catalyzed reaction of α-aryl-α,ß-unsaturated amides with ß-substituted acrylates proceeded to give formal conjugate adducts in high yield and ee (up to 99% yield and up to 95% ee). This is the first example of the enantioselective cross-coupling of two different electron-deficient alkenes via vinylic sp2 C-H activation, and polyfunctionalized chiral compounds were obtained.

Exploring the applicability of the robotic seal PARO to support caring for older persons with dementia within the home context.

OBJECTIVE: To (1) examine the potentiality of using the robot PARO to mediate care provided by the family and (2) identify problems when utilizing PARO in the home context. METHODS: Family members of 7 households were asked to use PARO for at least three times per week, over 1 to 3 months. Research data, including standardized assessments, interviews, and observations, were collected at initial and subsequent monthly visits. Collected data were analyzed through descriptive statistics and inductive thematic content analysis. RESULTS: Out of the seven participants, five responded positively to PARO, thereby achieving their goals of improving activity engagement, relaxation, a respite from supervision, and improved mood. A positive initial interaction with PARO showed continued interest to it. Participants were observed to communicate with caregivers and relate to PARO. DISCUSSION: The application of PARO at home is possibly influenced by the persons' initial level of interest toward PARO. It is crucial to perform careful observation and assessment before deciding to use PARO within the home context to support the life of older persons with dementia.

Ni-catalyzed non-activated C-S bond cleavage at ambient temperature for the synthesis of sulfur-containing polycyclic compounds.

A Ni-catalyzed intramolecular reaction of diarylthioether-tethered 1,8-diynes gave sulfur-containing tetracyclic compounds at ambient temperature. The transformation was initiated by non-activated sp2 C-S bond cleavage along with consecutive alkyne insertions. A double intramolecular reaction of a tetrayne and an intermolecular reaction of monoynes were also available, and the corresponding polycyclic compounds were obtained. Moreover, the obtained cycloadduct showed photo-catalytic activity in benzylic oxidation.

Gold-catalyzed dual C-C bond cleavage of biphenylenes bearing a pendant alkyne at ambient temperature.

We report a catalytic skeletal rearrangement of biphenylenes with a pendant alkyne moiety at room temperature by a cationic gold catalyst, which involves the cleavage of two bonds: the C-C bond of biphenylene and the C(sp)-C(sp2 or sp3) bond. Experimental and theoretical studies revealed that the reaction mechanism included π-activation of the alkyne, ring expansion and 1,2-carbon shift.

A cross-sectional analysis of clinicopathologic similarities and differences between Henoch-Schönlein purpura nephritis and IgA nephropathy.

INTRODUCTION: Recent studies noted that Henoch-Schönlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) share the feature of galactose-deficient IgA1 (Gd-IgA1)-oriented pathogenesis, although there are distinct clinical differences. We aimed to clarify the clinicopathologic differences between these 2 diseases. METHODS: We cross-sectionally analyzed adult patients with HSPN (n = 24) or IgAN (n = 56) who underwent renal biopsy (RB) between 2008 and 2018 at Showa University Hospital. Serum Gd-IgA1 (s-Gd-IgA1) levels at the time of RB were compared among study groups using enzyme-linked immunosorbent assay (ELISA) with anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for glomerular Gd-IgA1 (g-Gd-IgA1)-deposition using KM55. Serum inflammatory cytokines were measured using ELISA. RESULTS: Glomerular endothelial injury with subendothelial IgA deposition was significant in patients with HSPN. Serum IL-8, MCP-1, TNF-α, and IL-6 levels were significantly higher in patients with HSPN than IgAN. Levels of s-Gd-IgA1 were comparable among patients with HSPN and IgAN, and a similar degree of g-Gd-IgA1-deposition was detected in both diseases. Furthermore, g-Gd-IgA1-deposition was evident in patients with histopathologically advanced HSPN or IgAN. In HSPN, significant positive correlations between s-Gd-IgA1 levels and crescent formation or IL-6 elevation were confirmed, and g-Gd-IgA1 intensity showed a significant positive correlation with MCP-1 and a tendency to positively correlate with IL-8. Meanwhile, patients with IgAN showed no correlation between inflammatory cytokines and both-Gd-IgA1. Moreover, most g-Gd-IgA1-positive areas were not double stained with CD31 in HSPN. CONCLUSIONS: Although assessing both-Gd-IgA1 alone was insufficient to distinguish between HSPN and IgAN, patients with HSPN showed considerable glomerular capillaritis with subendothelial IgA deposition and significant elevation of serum inflammatory cytokines. Furthermore, such glomerular subendothelial IgA deposition might not contain Gd-IgA1, and factors associated with Gd-IgA1 were inconsistent among these 2 diseases. Thus, developmental mechanisms for IgAN might not apply to HSPN completely, and these 2 diseases still have different aspects.

Short-step synthesis and chiroptical properties of polyaza[5]-[9]helicenes with blue to green-colour emission.

We have developed a two- or three-step synthesis of polyaza[5]-[9]helicenes by consecutive N-H/C-H coupling with a hypervalent iodine reagent. We further evaluated their photophysical properties, and circularly polarized luminescence properties and found that glum values increase with the number of fused rings up to 2.7 × 10-2, which is the highest value among [9]helicenes.

Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) was approved in 2008 and has been used for treatment of disseminated intravascular coagulation in Japan. The antifibrotic effects of rhTM in acute exacerbation of idiopathic pulmonary fibrosis are well established, but the therapeutic potential of rhTM in renal fibrosis remains poorly understood. METHODS: Nephrotoxic serum nephritis (NTS-N) was induced in 22 female Wistar-Kyoto (WKY) rats on day 0. Rats were administered either rhTM or vehicle intraperitoneally, every day from day 4 to day 55. Rats were sacrificed on day 56 when renal fibrosis was established and renal morphological investigations were performed. In vitro, rat renal fibroblasts (NRK-49F) were pretreated with rhTM or saline, and expression levels of profibrogenic gene induced by thrombin were analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: Compared to WKY-GN-vehicle rats, the body weights of WKY-GN-rhTM rats were significantly greater on day 55. By day 56, rhTM had significantly reduced serum creatinine levels in NTS-N. On the other hand, urinary protein excretion was comparable between the two treatment groups throughout the study. The percentage of Masson trichrome-positive areas in WKY-GN-rhTM rats was significantly lower compared to that in WKY-GN-vehicle rats. Glomerular fibrin deposition was significantly reduced in WKY-GN-rhTM rats. In addition, rhTM significantly reduced the renal cortical mRNA expression levels of TNF-α, Toll-like receptor 4, MYD88, TGF-ß, αSMA, collagen I, collagen III, fibronectin, and protease-activated receptor 1 (PAR1), a thrombin receptor. In vitro, thrombin stimulation of NRK-49F cells significantly enhanced the mRNA expression levels of αSMA and PAR1, and these upregulations were significantly reduced by pretreatment with rhTM. CONCLUSIONS: Administration of rhTM after establishment of crescentic glomerulonephritis (GN) attenuated the subsequent development of renal fibrosis in NTS-N, possibly in part by inhibiting thrombin-mediated fibrogenesis. Our results suggest that rhTM may offer a therapeutic option for limiting the progression of chronic kidney disease in crescentic GN.

Crescentic IgA nephropathy after administration of human monoclonal interleukin-12/23p40 antibody in a patient with Crohn's disease: a case report.

Ustekinumab (UST), an interleukin (IL)-12/IL-23-blocking monoclonal antibody, is a novel therapeutic option for Crohn's disease (CD). We describe a 24-year-old man with CD who showed an abrupt decline in renal function after administration of UST. Twenty-nine months previously, the patient was diagnosed with CD, and abnormal urinalysis findings in health checkup were coincidentally found at that time. Three months previously, treatment for CD was switched from infliximab to UST because of therapy-resistant severe diarrhea and bloody stools. A single dose of UST (260 mg) was initially intravenously administered, followed by single subcutaneous administration (90 mg) 2 months later. Thereafter, the patient exhibited rapid renal dysfunction with significant urinary abnormalities, although his gastrointestinal symptoms had completely disappeared. He was admitted to our hospital for further examination and treatment. Renal pathologic findings were compatible with crescentic glomerulonephritis consisting of almost fibro-cellular crescents. Immunofluorescent study showed IgA and C3 deposition in the glomerular mesangial area and IgA subclass staining revealed predominant IgA1 with concomitant mild IgA2 deposition. Furthermore, galactose-deficient IgA1 (Gd-IgA1) was also positive in the mesangial area. In addition, serum-Gd-IgA1 level was moderately increased. UST treatment was stopped and he responded to intensive steroid therapy with a parallel reduction of serum creatinine and Gd-IgA1 levels without flare of gastrointestinal symptoms. To our knowledge, this is the first case of immunoglobulin A nephropathy (IgAN) in patient with CD that might be aggravated by UST treatment. We presume that inhibition of IL-12/23 signaling with UST may cause to form crescentic IgAN by enhancing Gd-IgA1 production.

Catalytic Enantioselective Synthesis of Axially Chiral Polycyclic Aromatic Hydrocarbons (PAHs) via Regioselective C-C Bond Activation of Biphenylenes.

Chiral polycyclic aromatic hydrocarbons (PAHs) are expected to have unusual physical properties due to their chirality and expanded π-conjugated system. Indeed, PAHs are promising compounds as chiral recognizers and organic semiconductors. Therefore, an efficient method for the synthesis of chiral PAHs is strongly desired. In contrast to helically chiral PAHs, there are only limited examples of the enantioselective synthesis of axially chiral PAHs. Herein, we report the catalytic enantioselective synthesis of benzo[b]fluoranthene-based axially chiral PAHs in excellent yields and enantioselectivities (up to >99%, >99% ee) by regioselective cleavage of the sterically hindered C-C bond of biphenylenes. The consecutive cyclizations could provide polycyclic PAHs with two chiral axes. The obtained chiral PAHs have high ε values (up to ε = 8.9 × 104), quantum yields (up to Φ = 0.67), and circularly polarized luminescence (CPL) property (|glum| = up to 3.5 × 10-3).

Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography-tandem mass spectrometry.

AIM: Laser microdissection (LMD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) enable clinicians to analyse proteins from tissue sections. In nephrology, these methods are used to diagnose diseases of abnormal protein deposition, such as amyloidosis, but they are seldom applied to the diagnosis and pathophysiological understanding of human glomerular diseases. METHODS: Renal biopsy specimens were obtained from five patients with IgA nephropathy (IgAN), five patients with membranous nephropathy (MN) and five kidney transplant donors (as controls). From 10-µm-thick sections of formalin-fixed, paraffin-embedded specimens, 0.3-mm2 samples of glomerular tissue were subjected to LMD. The samples were analysed by LC-MS/MS and investigated clinically and histologically. RESULTS: From the control glomeruli, we identified more than 300 types of proteins. In patients with IgAN, we detected significant increases not only in IgA1 and in C3, but also in the factors related to oxidative stress and cell proliferation in comparison to the controls. In patients with MN, levels of IgG1, IgG4, C3, C4a and phospholipase-A2-receptor were significantly elevated in comparison to the controls, as were the aforementioned factors related to oxidative stress and cell proliferations detected in IgAN. CONCLUSION: Application of LMD and LC-MS/MS to renal biopsy specimens enabled us to identify not only pathognomonic proteins for the diagnosis, but also several factors possibly involved in the pathogenesis of human glomerular diseases.