Development and validation of a novel overhead method for anteroposterior radiographs of fractured rat femurs.

We aimed to establish a new method of obtaining femur anteroposterior radiographs from live rats. We used five adult male Sprague-Dawley rats and created a femoral fracture model with an 8 mm segmental fragment. After the surgery, we obtained two femoral anteroposterior radiographs, a novel overhead method, and a traditional craniocaudal view. We obtained the overhead method three times, craniocaudal view once, and anteroposterior radiograph of the isolated femoral bone after euthanasia. We compared the overhead method and craniocaudal view with an isolated femoral anteroposterior view. We used a two-sample t-test and intraclass correlation coefficient (ICC) to estimate the intra-observer reliability. The overhead method had significantly smaller differences than the craniocaudal view for nail length (1.53 ± 1.26 vs. 11.4 ± 3.45, p < 0.001, ICC 0.96) and neck shaft angle (5.82 ± 3.8 vs. 37.8 ± 5.7, p < 0.001, ICC 0.96). No significant differences existed for intertrochanteric length/femoral head diameter (0.23 ± 0.13 vs. 0.23 ± 0.13, p = 0.96, ICC 0.98) or lateral condyle/medial condyle width (0.15 ± 0.16 vs. 0.13 ± 0.08, p = 0.82, ICC 0.99). A fragment displacement was within 0.11 mm (2.4%). The overhead method was closer to the isolated femoral anteroposterior view and had higher reliability.

Association of Head-Neck Rotation With History of Pitching-Related Elbow Pain in Youth Baseball Players.

Background: Prevention of pitching-related elbow pain in youth baseball players is important. Overhead pitching involves a whole-body motion, including head-neck rotation. A limited range of motion of head-neck rotation may cause inefficient pitching motion; however, this association is unclear. Purpose: To determine whether the range of motion of head-neck rotation is associated with the history of pitching-related elbow pain in youth baseball players. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 311 youth baseball players were selected and asked to complete a questionnaire survey about their age, weight, height, sex, baseball experience, main position, pitching side, and previous/current elbow pain during pitching. The range of motion of the upper and lower limb joints, head-neck rotation, and thoracic kyphosis angle were measured. Binomial logistic regression analysis was used to identify factors associated with the history of elbow pain related to pitching. Results: There were 101 players with a history of pitching-related elbow pain (history group) and 142 players with no pitching-related elbow pain (no-history group). The history group had significantly lower values than the no-history group regarding the range of motion of head-neck rotation on the nondominant side (74.9°± 9° vs 77.7°± 9.6°; P = .02) and overall head-neck rotation (150.6°± 14.7° vs 154.9°± 18.4°; P = .04). Binomial logistic regression analysis identified head-neck rotation on the nondominant side (odds ratio [OR], 0.97 [95% CI, 0.94-1.00]), shoulder horizontal adduction on the dominant side (OR, 0.98 [95% CI, 0.96-1.00]), height (OR, 1.04 [95% CI, 1.00-1.08]), and playing position (pitcher) (OR, 0.40 [95% CI, 0.21-0.76]) as factors associated with a history of pitching-related elbow pain. Conclusion: Our cross-sectional analysis demonstrated that youth baseball players with a history of pitching-related elbow pain had limited head-neck rotation range of motion on the nondominant side, and this was a significant factor associated with the history of pitching-related elbow pain.

Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

Phase engineering of anomalous Josephson effect derived from Andreev molecules.

A Josephson junction (JJ) is a key device for developing superconducting circuits, wherein a supercurrent in the JJ is controlled by the phase difference between the two superconducting electrodes. When two JJs sharing one superconducting electrode are coherently coupled and form the Andreev molecules, a supercurrent of one JJ is expected to be nonlocally controlled by the phase difference of another JJ. Here, we evaluate the supercurrent in one of the coupled two JJs as a function of local and nonlocal phase differences. Consequently, the results exhibit that the nonlocal phase control generates a finite supercurrent even when the local phase difference is zero. In addition, an offset of the local phase difference giving the JJ ground state depends on the nonlocal phase difference. These features demonstrate the anomalous Josephson effect realized by the nonlocal phase control. Our results provide a useful concept for engineering superconducting devices such as phase batteries and dissipationless rectifiers.

Phase-dependent Andreev molecules and superconducting gap closing in coherently-coupled Josephson junctions.

The Josephson junction (JJ) is an essential element of superconducting (SC) devices for both fundamental and applied physics. The short-range coherent coupling of two adjacent JJs forms Andreev molecule states (AMSs), which provide a new ingredient to engineer exotic SC phenomena such as topological SC states and Andreev qubits. Here we provide tunneling spectroscopy measurements on a device consisting of two electrically controllable planar JJs sharing a single SC electrode. We discover that Andreev spectra in the coupled JJ are highly modulated from those in the single JJs and possess phase-dependent AMS features reproduced in our numerical calculation. Notably, the SC gap closing due to the AMS formation is experimentally observed. Our results help in understanding SC transport derived from the AMS and promoting the use of AMS physics to engineer topological SC states and quantum information devices.

Alteration of Interhemispheric Inhibition in Patients With Lateral Epicondylalgia.

Patients with lateral epicondylalgia (LE) show alterations in the primary motor cortex (M1) contralateral to the affected side. Cortical alterations have been investigated by measuring intracortical facilitation/inhibition; however, their association with pain remains controversial. Furthermore, no studies have investigated changes in interhemispheric inhibition (IHI). IHI can be assessed using the ipsilateral silent period (iSP) known as the temporary inhibition of electromyographic activity evoked by transcranial magnetic stimulation in the ipsilateral M1 of the contracting muscle. To better understand the relationship between cortical alterations and pain in LE, this observational study investigated the relationship between iSP and pain in LE. Twenty-seven healthy volunteers and 21 patients with LE were recruited. The duration of iSP in the extensor carpi radialis brevis was measured. The IHI asymmetry ratio was calculated to determine the IHI balance. Pain and disability were scored using the Japanese version of the patient-rated elbow evaluation. We observed increased inhibitory input from the ipsilateral M1 on the affected side to the contralateral M1 in LE. Additionally, the IHI balance correlated with pain severity. Hence, regulating imbalanced IHI can potentially decrease lateral elbow pain in LE. PERSPECTIVE: Patients with lateral epicondylalgia (LE) experience persistent pain and cortical alterations. However, there is no established relationship between cortical alterations and pain. This study demonstrated that the interhemispheric inhibition (IHI) balance is correlated with pain. Regulating imbalanced IHI can potentially decrease lateral elbow pain in patients with LE.

Signal conversion as tumor micro environment (TME) specifically activated cytokine.

Targeted cytokine delivery has been gaining popularity in cancer immunotherapy since systemic recombinant cytokine treatment has not been successful due to low response rate and systemic toxicities in the clinical studies. In order to address these issues, we propose a new concept that cytokine signal is specifically activated at tumor-micro-environment (TME) by delivering two protein subunits of heterodimeric cytokine fused with a tumor targeting antibody respectively to TME and by bridging the two subunits into active heterodimeric form.Interleukin-12 (IL-12) is one of the major cytokines which can induce immune activation. IL-12 consists of two protein subunits which are p35 and p40. IL-12 signaling is initiated when it forms as the heterodimeric protein and binds to IL-12 receptor complex. We made fusion proteins of both IL-12p35 and IL-12p40 targeting specific tumor associated antigens (TAAs) and demonstrated the formation of bioactive IL12p70 with TME targeting antibody toward both p35 and p40 to form as the active molecule. We describe our concept validation in an in vitro based functional assay.

Resting-state functional connectivity disruption between the left and right pallidum as a biomarker for subthreshold depression.

Although the identification of late adolescents with subthreshold depression (StD) may provide a basis for developing effective interventions that could lead to a reduction in the prevalence of StD and prevent the development of major depressive disorder, knowledge about the neural basis of StD remains limited. The purpose of this study was to develop a generalizable classifier for StD and to shed light on the underlying neural mechanisms of StD in late adolescents. Resting-state functional magnetic resonance imaging data of 91 individuals (30 StD subjects, 61 healthy controls) were included to build an StD classifier, and eight functional connections were selected by using the combination of two machine learning algorithms. We applied this biomarker to an independent cohort (n = 43) and confirmed that it showed generalization performance (area under the curve = 0.84/0.75 for the training/test datasets). Moreover, the most important functional connection was between the left and right pallidum, which may be related to clinically important dysfunctions in subjects with StD such as anhedonia and hyposensitivity to rewards. Investigation of whether modulation of the identified functional connections can be an effective treatment for StD may be an important topic of future research.

Factors Related to the Delayed Cure of Hemifacial Spasm after Microvascular Decompression: An Analysis of 175 Consecutive Patients.

Detailed studies assessing the factors related to delayed cure of hemifacial spasm (HFS) after microvascular decompression (MVD) are sparse. We aimed to evaluate the effect of 11 clinical factors on the time until the patient became spasm free after MVD. We enrolled 175 consecutive patients with HFS who underwent MVD between 2012 and 2018. The end point was defined as the time point at which the patient became spasm free based on the outpatient interview. Patients were divided into six groups depending on when they became spasm free after the operation, as follows: <7 days ( n = 62), 7 days to 1 month ( n = 28), 1 to 3 months ( n = 38), 3 to 6 months ( n = 25), 6 to 12 months ( n = 17), and >12 months ( n = 5). The median time to become spasm free after MVD was 30.0 days. Association of 11 factors (age, sex, laterality, number of offending arteries, vertebral artery compression, number of compression sites, compression at root detachment zone, preoperative Botox treatment, indentation of the brain stem on preoperative magnetic resonance image, transposition, and interposition) with spasm-free rate was assessed using the Cox's proportional hazards model. Spasm-free rate curve after MVD for the significant factor was obtained using the Kaplan-Meier method. In univariate and multivariate analyses, nontransposition was significantly related to delayed HFS cure after MVD (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.42, 0.87; p = 0.0068 and HR, 0.60; CI, 0.43, 0.85; p = 0.042, respectively). The spasm-free rate was higher in the transposition than in the nontransposition group ( p = 0.0013). As shortening the time until spasm free after MVD improves patients' quality of life, transposition should be recommended. Prediction of spasm-free time could relieve the anxiety of postoperative patients.

Quasiparticle Trapping at Vortices Producing Josephson Supercurrent Enhancement.

The Josephson junction of a strong spin-orbit material under a magnetic field is a promising Majorana fermion candidate. Supercurrent enhancement by a magnetic field has been observed in the InAs nanowire Josephson junctions and assigned to a topological transition. In this work we observe a similar phenomenon but discuss the nontopological origin by considering the trapping of quasiparticles by vortices that penetrate the superconductor under a finite magnetic field. This assignment is supported by the observed hysteresis of the switching current when sweeping up and down the magnetic field. Our experiment shows the importance of quasiparticles in superconducting devices with a magnetic field, which can provide important insights for the design of qubits using superconductors.

Interictal High Gamma Oscillation Regularity as a Marker for Presurgical Epileptogenic Zone Localization.

BACKGROUND: To ensure that epilepsy surgery is effective, accurate presurgical localization of the epileptogenic zone is essential. Our previous reports demonstrated that interictal high gamma oscillation (30-70 Hz) regularity (GOR) on intracranial electroencephalograms is related to epileptogenicity. OBJECTIVE: To examine whether preoperative GOR analysis with interictal high-density electroencephalography (HD-EEG) improves the accuracy of epileptogenic focus localization and enhances postoperative seizure control. METHODS: We calculated GOR from 20 seconds of HD-EEG data for 21 patients with refractory focal epilepsy (4 with nonlesional temporal lobe epilepsy) scheduled for epilepsy surgery. Low-resolution brain electromagnetic tomography was used to analyze the high GOR source. To validate our findings, we made comparisons with other conventional localization methods and postoperative seizure outcomes. RESULTS: In all patients, the areas of interictal high GOR were identified and resected. All patients were seizure-free after the operation. The concordance between the results of interictal high GOR on HD-EEG and those of source estimation of interictal discharge was fully overlapping in 10 cases, partially overlapping in 8 cases, and discordant in 3 cases. The concordance between the results of interictal high GOR on HD-EEG and those of interictal 123 I-iomazenil single-photon emission computed tomography was fully overlapping in 8 cases, partially overlapping in 11 cases, and discordant in 2 cases. In 4 patients with nonlesional temporal lobe epilepsy, the interictal high GOR on HD-EEG was useful in confirming the epileptogenic zone. CONCLUSION: The interictal high GOR on HD-EEG is an excellent marker for presurgical epileptogenic zone localization.

Visualization of ictal networks using gamma oscillation regularity correlation analysis in focal motor epilepsy: Illustrative cases.

Background: Focal motor epilepsy is difficult to localize within the epileptogenic zone because ictal activity quickly spreads to the motor cortex through ictal networks. We previously reported the usefulness of gamma oscillation (30-70 Hz) regularity (GOR) correlation analysis using interictal electrocorticographic (ECoG) data to depict epileptogenic networks. We conducted GOR correlation analysis using ictal ECoG data to visualize the ictal networks originating from the epileptogenic zone in two cases - a 26-year-old woman with negative motor seizures and a 53-year-old man with supplementary motor area (SMA) seizures. Case Description: In both cases, we captured several habitual seizures during monitoring after subdural electrode implantation and performed GOR correlation analysis using ictal ECoG data. A significantly high GOR suggestive of epileptogenicity was identified in the SMA ipsilateral to the lesions, which were connected to the motor cortex through supposed ictal networks. We resected the high GOR locations in the SMA and the patients' previously identified tumors were removed. The patients were seizure-free without any neurological deficits after surgery. Conclusion: The GOR correlation analysis using ictal ECoG data could be a powerful tool for visualizing ictal networks in focal motor epilepsy.

Fc-independent functions of anti-CTLA-4 antibodies contribute to anti-tumor efficacy.

Ipilimumab, a monoclonal antibody that recognizes cytotoxic T-lymphocyte associated protein 4 (CTLA-4), was the first immune checkpoint inhibitor approved by the FDA to treat metastatic melanoma patients. Multiple preclinical studies have proposed that Fc effector functions of anti-CTLA-4 therapy are required for anti-tumor efficacy, in part, through the depletion of intratumoral regulatory T cells (Tregs). However, the contribution of the Fc-independent functions of anti-CTLA-4 antibodies to the observed efficacy is not fully understood. H11, a non-Fc-containing single-domain antibody (VHH) against CTLA-4, has previously been demonstrated to block CTLA-4-ligand interaction. However, in vivo studies demonstrated lack of anti-tumor efficacy with H11 treatment. Here, we show that a half-life extended H11 (H11-HLE), despite the lack of Fc effector functions, induced potent anti-tumor efficacy in mouse syngeneic tumor models. In addition, a non-Fc receptor binding version of ipilimumab (Ipi-LALAPG) also demonstrated anti-tumor activity in the absence of Treg depletion. Thus, we demonstrate that Fc-independent functions of anti-CTLA-4 antibodies contributed to anti-tumor efficacy, which may indicate that non-Treg depleting activity of anti-CTLA-4 therapy could benefit cancer patients in the clinic.

Evaluation of a carbapenem antimicrobial stewardship program and clinical outcomes in a Japanese hospital.

INTRODUCTION: Microorganisms can evolve and become resistant to antimicrobials, and this is known as antimicrobial resistance (AMR). Inappropriate use of antibiotics contributes to AMR, and antimicrobial stewardship programs have been developed to mitigate AMR. The Appropriate Use of Carbapenems Program was implemented in March 2019 in a university hospital and its effect was evaluated. METHODS: We conducted a prospective audit and feedback on carbapenems at the time of prescription daily. Additionally, we compared a monthly survey of the total days of therapy (DOTs) per 1000 patient-days for carbapenems, piperacillin/tazobactam, and fluoroquinolones. The susceptibility of Pseudomonas aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin was tested before (January 2018 to February 2019) and after (March 2019 to December 2020) the intervention. RESULTS: The monthly median DOTs of carbapenem usage decreased after the intervention; carbapenem use immediately declined during the intervention period. The monthly median DOTs of piperacillin/tazobactam and fluoroquinolones also decreased and continued to decline significantly after the intervention. Susceptibility of P. aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin did not change significantly during the study. CONCLUSION: The implementation of the Appropriate Use of Carbapenems Program was effective in reducing the use of broad-spectrum antibiotics and maintaining the antibiotic susceptibility of P. aeruginosa.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response.

BACKGROUND: Immune checkpoint blockade (ICB) therapies have changed the paradigm of cancer therapies. However, anti-tumor response of the ICB is insufficient for many patients and limited to specific tumor types. Despite many preclinical and clinical studies to understand the mechanism of anti-tumor efficacy of ICB, the mechanism is not completely understood. Harnessing preclinical tumor models is one way to understand the mechanism of treatment response. METHODS: In order to delineate the mechanisms of anti-tumor activity of ICB in preclinical syngeneic tumor models, we selected two syngeneic murine colorectal cancer models based on in vivo screening for sensitivity with anti-PD-1 therapy. We performed tumor-immune profiling of the two models to identify the potential mechanism for anti-PD-1 response. RESULTS: We performed in vivo screening for anti-PD-1 therapy across 23 syngeneic tumor models and found that CT-26 and Colon 26, which are murine colorectal carcinoma derived from BALB/c mice, showed different sensitivity to anti-PD-1. CT-26 tumor mice were more sensitive to the anti-PD-1 antibody than Colon 26, while both models show similarly sensitivity to anti-CTLA4 antibody. Immune-profiling showed that CT-26 tumor tissue was infiltrated with more immune cells than Colon 26. Genomic/transcriptomic analyses highlighted thatWnt pathway was one of the potential differences between CT-26 and Colon 26, showing Wnt activity was higher in Colon 26 than CT-26. . CONCLUSIONS: CT-26 and Colon 26 syngeneic tumor models showed different sensitivity to anti-PD-1 therapy, although both tumor cells are murine colorectal carcinoma cell lines from BALB/c strain. By characterizing the mouse cells lines and tumor-immune context in the tumor tissues with comprehensive analysis approaches, we found that CT-26 showed "hot tumor" profile with more infiltrated immune cells than Colon 26. Further pathway analyses enable us to propose a hypothesis that Wnt pathway could be one of the major factors to differentiate CT-26 from Colon 26 model and link to anti-PD-1 response. Our approach to focus on preclinical tumor models with similar genetic background but different sensitivity to anti-PD-1 therapy would contribute to illustrating the potential mechanism of anti-PD-1 response and to generating a novel concept to synergize current anti-PD-1 therapies for cancer patients.

Influences of Lavender Essential Oil Inhalation on Stress Responses during Short-Duration Sleep Cycles: A Pilot Study.

Lavender essential oil (LEO) was reported to improve sleep quality. We investigated the influence of aromatherapy by testing the effects of LEO on stress responses during a short-duration sleep in a single-blind, randomized, crossover trial. The subjects were twelve healthy adults who were nonsmokers without any known disease and who were not prescribed medications, and nine of these completed the study. After the subjects had fallen asleep, they were sprayed with LEO using an aroma diffuser. Before and after 90 min of sleep, α-amylase, chromogranin A (CgA), and cortisol levels in saliva were measured as objective stress indicators, and the Japanese version of the UWIST Mood Adjective Checklist was used as a subjective indicator. A comparison of changes before and after sleep, with and without LEO, revealed that the cortisol level did not significantly change; however, α-amylase (p < 0.05) and CgA (p < 0.01) levels significantly decreased after LEO inhalation. A mood test indicated no change in mood before and after sleep, with or without LEO. Since α-amylase and CgA reflect the sympathetic nervous system response, these results indicate that LEO aromatherapy during a short-duration sleep cycle suppresses the stress response, especially that of the sympathetic nervous system.

Intraoperative epileptogenic network visualization using gamma oscillation regularity correlation analysis in epilepsy surgery.

BACKGROUND: We have recently demonstrated that gamma oscillation (30-70 Hz) regularity (GOR) analysis accurately localized epileptogenic focus using intraoperative electrocorticographic data. In this report, we assessed whether GOR correlation analysis could depict epileptogenic networks intraoperatively. Dual foci in temporal lobe epilepsy without hippocampal structural abnormalities are difficult to diagnose. Using our GOR correlation analysis, we aimed to intraoperatively visualize such dual foci and epileptogenic networks. CASE DESCRIPTION: A 56-year-old man suffered from pharmacoresistant focal impaired awareness seizures. Magnetic resonance imaging demonstrated an 8 × 12-mm cavernoma in the right inferior temporal gyrus without any structural changes in the hippocampus. Since ictal semiology indicated a high probability of epileptogenicity in the right hippocampus, we reached the hippocampus using a transsylvian approach and assessed intraoperative GOR correlation analysis in the lateral temporal lobe where the cavernoma was located and the hippocampus, simultaneously. High GORs suggestive of epileptogenicity were identified in both the lateral temporal lobe and the hippocampus. Furthermore, they were connected using GOR correlation networks. When the high GOR locations in the lateral temporal lobe and the cavernoma were removed, high GORs and those networks were found within the hippocampus only. After additional hippocampal transection, high GORs and these networks were absent. The patient became seizure-free after the surgery. CONCLUSION: Our GOR correlation analysis may be a powerful tool for intraoperative evaluation of epileptogenic networks in epilepsy surgery.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Synthesis and Properties of Spiro-double Sila[7]helicene: The LUMO Spiro-conjugation.

A double helicene with a spiro-Si linker (4) was synthesized by four successive nucleophilic substitutions on SiCl4 . Its (P,P), (M,M) and (P,M) isomers were isolated and characterized by single crystal X-ray analysis. Due to the central spirosilabi[fluorene] moiety, the two helicene units in 4 are symmetrically and nearly perpendicularly arranged. (P,P)-4 and (M,M)-4 exhibit unique optical properties attributable to the LUMO spiro-conjugation between the two sila[7]helicene units.