BackgroundNot all non-small cell lung cancer (NSCLC) patients possess drug-targetable driver mutations, and response rates to immune checkpoint blockade therapies also remain unsatisfactory. Therefore, more effective treatments are still needed. Here, we report the results of a phase 2 clinical trial of adoptive cell therapy using zoledronate-expanded autologous Vγ9Vδ2 T-cells for treatment-refractory NSCLC.MethodsNSCLC patients who had undergone at least two regimens of standard chemotherapy for unresectable disease or had had at least one treatment including chemotherapy or radiation for recurrent disease after surgery were enrolled in this open-label, single-arm, multicenter, phase 2 study. After preliminary testing of Vγ9Vδ2 T-cell proliferation, autologous peripheral blood mononuclear cells were cultured with zoledronate and IL-2 to expand the Vγ9Vδ2 T-cells. Cultured cells (>1×109) were intravenously administered every 2 weeks for six injections. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), best objective response rate (ORR), disease control rate (DCR), safety and immunomonitoring. Clinical efficacy was defined as median PFS significantly >4 months.ResultsTwenty-five patients (20 adenocarcinoma, 4 squamous cell carcinoma and 1 large cell carcinoma) were enrolled. Autologous Vγ9Vδ2 T-cell therapy was administered to all 25 patients, of which 16 completed the foreseen course of 6 injections of cultured cells. Median PFS was 95.0 days (95% CI 73.0 to 132.0 days); median OS was 418.0 days (179.0–479.0 days), and best overall responses were 1 partial response, 16 stable disease (SD) and 8 progressive disease. ORR and DCR were 4.0% (0.1%–20.4%) and 68.0% (46.5%–85.1%), respectively. Severe adverse events developed in nine patients, mostly associated with disease progression. In one patient, pneumonitis and inflammatory responses resulted from Vγ9Vδ2 T-cell infusions, together with the disappearance of a massive tumor.ConclusionsAlthough autologous Vγ9Vδ2 T-cell therapy was well tolerated and may have an acceptable DCR, this trial did not meet its primary efficacy endpoint.Trial registration numberUMIN000006128
The coinhibitory receptor, PD-1, is of major importance for the suppression of T cell activation in various types of immune responses. A high-resolution imaging study showed that PD-1 forms a coinhibitory signalosome, “PD-1 microcluster”, with the phosphatase, SHP2, to dephosphorylate the TCR/CD3 complex and its downstream signaling molecules. Such a consecutive reaction entirely depended on PD-1–PD-L1/2 binding. PD-L2 is expressed on professional antigen-presenting cells and also on some tumor cells, which possibly explains the discrepant efficacy of immune checkpoint therapy for PD-L1-negative tumors. Here, we performed precise imaging analysis of PD-L2 forming PD-1–PD-L2 clusters associating with SHP2. PD-L2 could compete with PD-L1 for binding to PD-1, occupying the same space at TCR microclusters. The PD-1 microcluster formation was inhibited by certain mAbs with functional consequences. Thus, PD-1 microcluster formation provides a visible index for the effectiveness of anti-PD-1- or anti-PD-L1/2-mediated T cell suppression. PD-L2 may exert immune suppressive responses cooperatively with PD-L1 on the microcluster scale.
Background Helicobacter cinaedi is a microaerobic Gram-negative spiral-shaped bacterium that causes enteritis, cellulitis, and bacteremia in both immunocompromised and immunocompetent patients. While there have been increasing numbers of reported H. cinaedi infections recently, there has been no thyroid abscess case caused by H. cinaedi presenting with thyroid storm. Case presentation A 50-year-old Japanese man presented with a 9-day history of high fever associated with palpitations, dry cough, and chronic diarrhea. The patient had a history of Basedow’s disease that had been treated with thiamazole in the past. During the current episode, the patient was diagnosed with thyroid storm and treated accordingly. The blood culture taken on admission was positive for H. cinaedi . This finding was confirmed by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOFMS). A systemic computed tomography (CT) scan revealed a thyroid abscess as the site of infection and cause of the bacteremia. The 16S rRNA gene sequencing identified the pathogen of thyroid abscess as H. cinaedi . Clinical symptoms and laboratory data normalized on admission day 7 after treatment with both effective antibiotics and antithyroid drugs. Conclusions The case study described a patient with a history of Basedow’s disease that presented with a thyroid abscess caused by H. cinaedi with symptoms similar to those of thyroid storm. While this bacterium has been implicated in other infections, we believe this is the first time the bacteria has been documented to have caused a thyroid abscess. Electronic supplementary material The online version of this article (10.1186/s12879-019-3808-7) contains supplementary material, which is available to authorized users.
Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating transcription factor) family transcription factors. Nurr1 belongs to the NR4A family and is regarded as an orphan nuclear receptor. The physiological significance of Nurr1 in aldosterone production in adrenal cortex has been well studied. However, coregulators supporting the Nurr1 function still remain elusive. In this study, we performed RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), a recently developed endogenous coregulator purification method, in human adrenocortical H295R cells and identified PARP1 as one of the top Nurr1-interacting proteins. Nurr1-PARP1 interaction was verified by co-immunoprecipitation. In addition, both siRNA knockdown of PARP1 and treatment of AG14361, a specific PARP1 inhibitor suppressed the angiotensin II-mediated target gene induction in H295R cells. Furthermore, PARP1 inhibitor also suppressed the aldosterone secretion in response to the angiotensin II. Together, these results suggest PARP1 is a prime coregulator for Nurr1.
With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments.
Herb supplies can become unstable because of climate change and the economic development of herb exporters. In this paper, in order to increase the self-sufficiency of herbal resources we examined the possibility of changing to herb crop production from tobacco, for which demand is declining. Firstly, we considered demand, quality and the price of raw herb materials to make recommendations for corrections, and selected Angelica (A.) acutiloba and Bupleurum (B.) falcatum Linne. Next, we compared the profitability of tobacco and the herbs. Profit margins for A. acutiloba were less than for tobacco. It was thought that the profitability of A. acutiloba could become equivalent to tobacco if an adjustment subsidy were provided. The self-sufficiency rate for A. acutiloba would be one hundred percent with 35 million yen in every year. Although the profitability of B. falcatum has exceeded tobacco, its selling price was about 3 times that of imports, while the price of medical B. falcatum was lower than its selling price. It was thought that the price competitiveness problem of B. falcatum can be covered if a production subsidy is provided, and to reach a 50 percent B. falcatum selfsufficiency rate with 660 million yen per year.
With recent advances in immune checkpoint inhibitors (ICIs), cancer immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined on the basis of several clinical trials conducted separately. In this study, we have established an advanced imaging system to visualize “human PD-1 microclusters,” in which PD-1 actually dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2. Furthermore, each antibody required its own concentration and gained much greater effects in combination with other antibodies against different targets. We propose that our imaging system could digitally evaluate the PD-1-mediated T cell suppression and practical effects of each ICI. Currently, numerous new ICIs are tested, and more suitable combinations of them with other ICIs or conventional cancer treatments are being explored. Our study will have a wide range of applications to clinical practice in the future.
The purpose of the present study was to evaluate the clinical profiles and treatment outcomes of patients with lung cancer admitted to the Medical Psychiatric Unit (MPU), which is built for patients with physical and severe psychiatric disorders. All medical records of patients with lung cancer admitted to the MPU of Tachikawa hospital were reviewed. The clinical outcomes of these patients were retrospectively evaluated between January 2010 and December 2016. A total of 24 patients in the MPU were histologically or cytologically diagnosed with primary lung cancer. Of these, 20 patients had schizophrenia, and 4 patients had a mood disorder. There were 15 patients who were diagnosed using bronchoscopy. The histology indicated adenocarcinoma, squamous cell carcinoma and non-small-cell lung cancer-not otherwise specified were in 11, 8, and 1 patient, respectively, while small-cell lung cancer was indicated in 4 patients. Surgery, chemoradiotherapy, radiotherapy, chemotherapy was performed in 13, 4, 2, 1 and 4 patients, respectively. The median survival time was 76.7 months for patients who underwent surgery, while it was 14.4 months for those who underwent chemoradiotherapy. In the MPU, patients with lung cancer and severe psychiatric disorders could be safely diagnosed, and patients with early-stage lung cancer exhibited long-term survival.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.