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There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus. LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0–2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing. Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2–55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6–49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1–73·7) in the combination group. The most common grade 1–2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3–4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related. The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids. Novartis Pharma AG.

The thymus plays a pivotal role in generating a highly-diverse repertoire of T lymphocytes while preventing autoimmunity. Thymus seeding progenitors (TSPs) are a heterogeneous group of multipotent progenitors that migrate to the thymus via CCR7 and CCR9 receptors. While NOTCH guides thymus progenitors toward T cell fate, the absence or disruption of NOTCH signaling renders the thymus microenvironment permissive to other cell fates. Following T cell commitment, developing T cells undergo multiple selection checkpoints by engaging with the extracellular matrix, and interacting with thymic epithelial cells (TECs) and other immune subsets across the different compartments of the thymus. The different selection checkpoints assess the T cell receptor (TCR) performance, with failure resulting in either repurposing (agonist selection), or cell death. Additionally, environmental cues such as inflammation and endocrine signaling induce acute thymus atrophy, contributing to the demise of most developing T cells during thymic selection. We discuss the occurrence of acute thymus atrophy in response to systemic inflammation. The thymus demonstrates high plasticity, shaping inflammation by abrogating T cell development and undergoing profound structural changes, and facilitating regeneration and restoration of T cell development once inflammation is resolved. Despite the challenges, thymic selection ensures a highly diverse T cell repertoire capable of discerning between self and non-self antigens, ultimately egressing to secondary lymphoid organs where they complete their maturation and exert their functions.

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

The development of mesothelin (MSLN) epitope reactive T cells is observed in mice that are immunized with the MSLN vaccine. Engineered T cells expressing MSLN‐reactive high‐affinity TCR exhibit extraordinary therapeutic effects for invasive pancreatic ductal adenocarcinoma in a mouse model. However, the generation of MSLN‐reactive T cells through the introduction of MSLN‐deficient thymus and the transplantation of the latter as a cure for cancer treatment have not been tested to date. In the present study, the expression of MSLN was mainly identified in medullary thymic epithelial cells (mTECs) but not in hematopoietic cells, cortical thymic epithelial cells (cTECs), endothelial cells, or fibroblast cells in the thymus. The increasement of activated T cells was observed in MSLN‐expressing tumors from MSLN‐deficient mice, indicating that MSLN‐reactive T cells had developed. Finally, in an AOM‐DSS‐induced mouse model of colorectal cancer (CRC), transplantation of MSLN‐deficient thymus repressed the progression of CRC, accompanied by an increased number of IFNγ‐expressing T lymphocytes in the tumors. The data from this study demonstrated that ectopic transplantation of MSLN‐deficient thymus induced MSLN‐specific antitumor responses to MSLN‐expressing tumors, and thus attenuated tumor progression. In the present study, mesothelin (MSLN) deficiency in thymus induced the development of MSLN reactive T cells that had anti‐tumor functions against MSLN‐expressing tumor cells. In AOM‐DSS induced mouse colorectal cancer model, transplantation of MSLN‐deficient thymus repressed the colorectal cancer progression with elevated number of IFNγ‐expressing T lymphocytes in tumors, and increased survival. Our data demonstrated that ectopic transplantation of MSLN‐deficient thymus induced MSLN‐specific antitumor responses to MSLN‐expressing tumors and attenuated tumor progression.

No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1–46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3–36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5–29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0–26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3–4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

Tumor angiogenesis is a key factor in the progression of thymic epithelial tumors (TETs). Activin A, a member of the TGFβ family, and its antagonist Follistatin are involved in several human malignancies and angiogenesis. We investigated Activin A and Follistatin in serum and tumor tissue of patients with TETs in relation to microvessel density (MVD), WHO histology classification, tumor stage and outcome. Membranous Activin A expression was detected in all tumor tissues of TETs, while Follistatin staining was found in tumor nuclei and cytoplasm. Patients with TETs presented with significantly higher Activin A and Follistatin serum concentrations compared to healthy volunteers, respectively. Follistatin serum concentrations correlated significantly with tumor stage and decreased to physiologic values after complete tumor resection. Follistatin serum concentrations correlated further with MVD and were associated with significantly worse freedom from recurrence (FFR). Low numbers of immature tumor vessels represented even an independent worse prognostic factor for FFR at multivariable analysis. To conclude, the Activin A - Follistatin axis is involved in the pathogenesis of TETs. Further study of Follistatin and Activin A in TETs is warranted as the molecules may serve as targets to inhibit tumor angiogenesis and tumor progression.

Radioresistant thymic cells encompass minor subsets of lymphoid precursors of T cells (TLPs), innate lymphoid cells (ILCs), as well as stromal-epithelial and endothelial populations. This review focuses on radioresistant TLPs and their regenerative and functional roles in thymic regeneration following damaging influences, particularly irradiation, as well as their secretory product, referred to as thymocyte growth factor (THGF). Retrospective analysis of experimental data assumes that THGF-producing and THGF-responsive cells correspond to the earliest stage of thymocyte precursors, double-negative (DN) TLPs, of CD117 - Thy-1 + Sca-1 + CD44 + CD25 - CD4 - CD8 - phenotype, and may be a target for thymic oncogenesis, when they are in the activated DN1→DN2 stage. Unique features of THGF-driven proliferation of these cells include a colchicine-resistant DNA synthesis and, presumably, the formation of a “daughter” cell pool within “mother” cell-like structures, as well as the formation of colony-cluster-like structures, which are presumably composed mainly of single activated mother DN1 and surrounding daughter TLPs progressing from DN2 to DN4 stage. This atypical proliferation mode may represent an evolutionarily conserved mechanism of “defended mitosis” and/or amitotic or endomitotic pathways division, protecting against radiation-induced injury and thus allowing the cell expansion. THGF, which is induced by γ-irradiation and appears essential for autocrine expansion of radioresistant TLPs, initiates a cascade that enables subsequent responsiveness to IL-7, SCF, IL-2, and additional cytokines. The presented analysis proposes the concept of intrathymic dormant stem cells, which become activated under extreme conditions, and insights into parallels between THGF-responsive cells and other radioresistant thymic populations, suggesting an integrated network of stromal and lymphoid elements that orchestrate thymic regeneration. Together, this review proposes a model in which THGF acts as a critical regulator of dormant intrathymic stem cells, enabling their activation, protected proliferation, and differentiation, and thereby contributing crucially to the lymphoid lineage of thymic regeneration after irradiation, in addition to the concept of the IL-22-dependent pathway of stromal-epithelial regeneration of intrathymic niches microenvironment.

Light is a crucial factor in plant growth and development. Plants exposed to light stress experience various effects on their growth. This research was conducted to investigate the effects of different light intensities on morpho-physiological traits, phytochemical compounds, and gene expression related to the biosynthesis of voletile in Thymus vulgaris L. The results demonstrated that light intensity (20, 50, 70 and 100%) had a significant impact on morpho-physiological characteristics, pigments content, antioxidant enzymes activities, as well as the content of MDA, H 2 O 2 , anthocyanin, thymol, carvacrol, phenols, flavonoids, essential oils, and monoterpenes. Moreover, the expression of the biosynthesis genes of monoterpene compounds was significantly influenced by light intensity. While an increase in light intensity led to higher leaf count (164.6%) and biomass (33.5%), it was accompanied by a decrease in leaf area, stem length, and internode length. The highest levels of chlorophyll a (4.92 mgg -1 FW) and b (1.75 mgg -1 FW), carotenoids (907.31 µ Mg -1 FW), MDA (9.93 µ Mg -1 FW), anthocyanin, SOD (29.62 Umg  − 1 Protein), thymol (41.2%), and carvacrol (4.46%) were observed at 70% treatment and decreased as light intensity increased. Also, H 2 O 2 , catalase and polyphenol oxidase activities, phenols, flavonoids, essential oils, and monoterpenes increased with higher light intensity, with the highest H 2 O 2 concentration recorded at 100% (4.43 fold). Importantly, key genes involved in monoterpene biosynthesis, including DXR , TPS , CYP71D178 , and CYP71D179 , exhibited significantly enhanced expression under full light conditions compared to other light intensities. In conclusion, increased light intensity stimulated the elevation of oxidative indicators, antioxidant activity and enhancing the expression of genes involved in phytochemical compound biosynthesis and consequently leading to the accumulation of volatile compounds in Thymus vulgaris L. Future research will focus on investigating the combined effects of various abiotic stresses at the field level and extending the stress duration to evaluate potential additive effects.

Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection 1 . Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses 1 , 2 . Antigen-specific recognition of intestinal microorganisms by T cells has previously been described 3 , 4 . Although the local environment shapes the differentiation of effector cells 3 – 5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens. In young mice, antigens from the gut microbiota are trafficked by CX3CR1 + dendritic cells from the gut to the thymus, where they induce the expansion of T cells that are specific to commensal microorganisms.

Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC 50 between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15–83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use ( n  = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1–9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2–25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.