Retrospective Analysis of the Clinical Usefulness of a Strut-Adjusted Volume Implant in a Single Center.

OBJECTIVE: Reports demonstrating the effectiveness and safety of strut-adjusted volume implants (SAVI) in Japan are limited. Therefore, this study aimed to compare the treatment outcomes of SAVI and whole-breast irradiation (WBI) at a single facility. MATERIALS AND METHODS: Data were retrospectively extracted from the medical records of patients treated with SAVI or WBI following partial mastectomy (Bp). Patients undergoing Bp, sentinel lymph node biopsy, and SAVI spacer insertion followed by brachytherapy with the SAVI device were compared to those followed with WBI. Local recurrence was assessed annually by physical examination, bilateral mammography, and breast ultrasonography. RESULTS: The SAVI and WBI groups comprised 53 and 113 patients, with a median age of 55 and 52 years, respectively; among them, 47 and 91 patients had a pathological tumor diameter ≤2 cm and six and 22 had a pathological tumor diameter >2 cm, respectively. Recurrence events, acute adverse events, and late adverse events were observed in the SAVI and WBI groups in 1 and 3 (p = 0.726), 24 and 79 (p = 0.01), and 24 and 18 patients (p = 0.00002), respectively, with median observation periods of 60.0 and 47.8 months, respectively. All adverse events were grades 1-2, with dermatitis being the most common in the acute phase. In the late phase, pigmentation was common in both groups. CONCLUSION: The local recurrence rate does not differ between SAVI and WBI within the relatively short-term follow-up period. Longer follow-up is required to confirm our results in the Japanese population.

SAVI catheter digitization impact: A single institution multiuser uncertainty study.

To assess the impact of Strut Adjusted Volume Implant (SAVI) catheter digitization variability on dosimetric evaluation parameters of HDR breast brachytherapy treatment plans. Four clinically approved SAVI cases were chosen for this digitization variability analysis. All patients were implanted with 6-1 SAVI device. Six experienced physicists independently digitized SAVI catheters. Plans utilizing significant peripheral loading were used for this study where SAVI catheters were near the chest wall and/or skin. After digitization was completed for each case by each physicist, the original clinical dwell times were copied over for comparison. This ensured that only variability among plans is the digitization of SAVI catheters by different users. The original plan that went through two physicists' checks and one physician's review was considered the "ground truth" plan to which all other plans were compared. Plans were evaluated on planning parameters for lumpectomy cavity's PTV_Eval D90, V150, V200 and for the OARs (Chest-Wall/Ribs and Skin), on D0.03cc, D0.1cc, D1cc, D2cc. Additionally, a visualization window setting-based uncertainty test was performed on the same 4 cases. Our results showed that the average and maximum dwell positional digitization uncertainties were 0.36 and 0.75 mm, respectively. Average PTV_Eval D90 was 97.11+/-2.93 %, V150 was 23.10+/-4.25 cc, V200 was 11.88+/-1.93 cc. All OAR constraints were met on all plans - Chest-Wall/Ribs (CW/Ribs) and Skin D0.03cc was 103.40+/-9.23 % and 93.60+/-6.14 %, respectively. Aggregate analysis across all plans shows a clinically nonsignificant spread around the mean for all parameters considered. The robustness of SAVI treatment plans to minor variation in catheter digitization was proved through our multiuser study. Our study showed that SAVI planning constraints are stable within reasonable variation of digitization differences. Such uncertainty analysis is useful in standardization of digitization practices in a department and in defining action levels on digitization fixing request during a 2nd check.

The common Sting1 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice.

The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.

Coastal Dune Vegetation Dynamism and Anthropogenic-Induced Transitions in the Mexican Caribbean during the Last Decade.

In the Mexican Caribbean, environmental changes, hydrometeorological events, and anthropogenic activities promote dynamism in the coastal vegetation cover associated with the dune; however, their pace and magnitude remain uncertain. Using Landsat 7 imagery, spatial and temporal changes in coastal dune vegetation were estimated for the 2011-2020 period in the Sian Ka'an Biosphere Reserve. The SAVI index revealed cover changes at different magnitudes and paces at the biannual, seasonal, and monthly timeframes. Climatic seasons had a significant influence on vegetation cover, with increases in cover during northerlies (SAVI: p = 0.000), while the topographic profile of the dune was relevant for structure. Distance-based multiple regressions and redundancy analysis showed that temperature had a significant effect (p < 0.05) on SAVI patterns, whereas precipitation showed little influence (p > 0.05). The Mann-Kendall tendency test indicated high dynamism in vegetation loss and recovery with no defined patterns, mostly associated with anthropogenic disturbance. High-density vegetation such as mangroves, palm trees, and shrubs was the most drastically affected, although a reduction in bare soil was also recorded. This study demonstrated that hydrometeorological events and climate variability in the long term have little influence on vegetation dynamism. Lastly, it was observed that anthropogenic activities promoted vegetation loss and transitions; however, the latter were also linked to recoveries in areas with pristine environments, relevant for tourism.

Development of nitroalkene-based inhibitors to target STING-dependent inflammation.

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a ß-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

Ocular complications of SAVI: A unique case of bilateral uveitis and retinal vasculitis.

Purpose: To describe a case of bilateral panuveitis in a patient with Stimulator of Interferon Genes (STING)-Associated Vasculitis with Onset in Infancy (SAVI). Observations: A 45-year-old patient diagnosed with SAVI presented bilateral panuveitis and uncontrolled secondary intraocular hypertension due to structural complications from uveitis. Multimodal imaging revealed the presence of intraretinal fluid and bilateral vasculitis. The patient was started with systemic methotrexate. Conclusions and importance: This case is essential to characterize ocular involvement in patients with SAVI. Awareness of these ocular manifestations is crucial for timely management and improvement of visual prognosis.

Endothelial cell expression of a STING gain-of-function mutation initiates pulmonary lymphocytic infiltration.

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.

STING-associated vasculopathy with onset in infancy (SAVI) presenting with skin lesions.

STING-associated vasculopathy with onset in infancy (SAVI) is caused by pathogenic gain-of-function variants in the gene TMEM173 (also named stimulator of interferon genes, STING1). This report details the case of an 11-year-old girl with SAVI who presented with skin-limited symptoms and discusses the phenotype-genotype correlations of the TMEM173 variant present in our patient. Treatment of SAVI focuses on preventing the development or progression of organ damage by reducing systemic inflammation. We summarize the available treatments for this syndrome.

Evaluating Radar Reflector Localisation in Targeted Axillary Dissection in Patients Undergoing Neoadjuvant Systemic Therapy for Node-Positive Early Breast Cancer: A Systematic Review and Pooled Analysis.

SAVI SCOUT® or radar reflector localisation (RRL) has proven accurate in localising non-palpable breast and axillary lesions, with minimal interference with MRI. Targeted axillary dissection (TAD), combining marked lymph node biopsy (MLNB) and sentinel lymph node biopsy (SLNB), is becoming a standard post-neoadjuvant systemic therapy (NST) for node-positive early breast cancer. Compared to SLNB alone, TAD reduces the false negative rate (FNR) to below 6%, enabling safer axillary surgery de-escalation. This systematic review evaluates RRL's performance during TAD, assessing localisation and retrieval rates, the concordance between MLNB and SLNB, and the pathological complete response (pCR) in clinically node-positive patients post-NST. Four studies (252 TAD procedures) met the inclusion criteria, with a 99.6% (95% confidence [CI]: 98.9-100) successful localisation rate, 100% retrieval rate, and 81% (95% CI: 76-86) concordance rate between SLNB and MLNB. The average duration from RRL deployment to surgery was 52 days (range:1-202). pCR was observed in 42% (95% CI: 36-48) of cases, with no significant migration or complications reported. Omitting MLNB or SLNB would have under-staged the axilla in 9.7% or 3.4% (p = 0.03) of cases, respectively, underscoring the importance of incorporating MLNB in axillary staging post-NST in initially node-positive patients in line with the updated National Comprehensive Cancer Network (NCCN) guidelines. These findings underscore the excellent efficacy of RRL in TAD for NST-treated patients with positive nodes, aiding in accurate axillary pCR identification and the safe omission of axillary dissection in strong responders.

Cost-Effectiveness of Radar Localisation Versus Wire Localisation for Wide Local Excision of Non-palpable Breast Cancer.

BACKGROUND: Wire localisation (WL) is the "gold standard" localisation technique for wide local excision (WLE) of non-palpable breast lesions but has disadvantages that have led to the development of wireless techniques. This study compared the cost-effectiveness of radar localisation (RL) to WL. METHODS: This was a single-institution study of 110 prospective patients with early-stage breast cancer undergoing WLE using RL with the SCOUT® Surgical Guidance System (2021-2023) compared with a cohort of 110 patients using WL. Margin status, re-excision rates, and surgery delays associated with preoperative localisation were compared. Costs from a third-party payer perspective in Australian dollars (AUD$) calculated by using microcosting, break-even point, and cost-utility analyses. RESULTS: A total of 110 WLEs using RL cost a total of AUD$402,281, in addition to the device cost of AUD$77,150. The average additional cost of a surgery delay was AUD$2318. Use of RL reduced the surgery delay rate by 10% (p = 0.029), preventing 11 delays with cost savings of AUD$25,496. No differences were identified in positive margin rates (RL: 11.8% vs. WL: 17.3%, p = 0.25) or re-excision rates (RL: 14.5% vs. WL: 21.8%, p = 0.221). In total, 290 RL cases are needed to break even. The cost of WLE using RL was greater than WL by AUD$567. There was a greater clinical benefit of 1.15 quality-adjusted life-years (QALYs) and an incremental cost-utility ratio of AUD$493 per QALY favouring RL. CONCLUSIONS: Routine use of RL was a more cost-effective intervention than WL. Close to 300 RL cases are likely needed to be performed to recover costs of the medical device. CLINICAL TRIAL REGISTRATION: ACTRN12624000068561.

Radar-Guided Localization and Resection for Metastatic Nodal and Soft Tissue Melanoma: A Single-Institution Retrospective Study.

BACKGROUND: Radar-guided localization (RGL) offers a wire-free, nonradioactive surgical guidance method consisting of a small percutaneously-placed radar reflector and handheld probe. This study investigates the feasibility, timing, and outcomes of RGL for melanoma metastasectomy. METHODS: We retrospectively identified patients at our cancer center who underwent RGL resection of metastatic melanoma between December 2020-June 2023. Data pertaining to patients' melanoma history, management, reflector placement and retrieval, and follow-up was extracted from patient charts and analyzed using descriptive statistics. RESULTS: Twenty-three RGL cases were performed in patients with stage III-IV locoregional or oligometastatic disease, 10 of whom had reflectors placed prior to neoadjuvant therapy. Procedures included soft tissue nodule removals (8), index lymph node removals (13), and therapeutic lymph node dissections (2). Reflectors were located and retrieved intraoperatively in 96% of cases from a range of 2 to 282 days after placement; the last reflector was not able to be located during surgery via probe or intraoperative ultrasound. One retrieved reflector had migrated from the index lesion, thus overall success rate of reflector and associated index lesion removal was 21 of 23 (91%). All RGL-localized and retrieved index lesions that contained viable tumor (10) had microscopically negative margins. There were no complications attributable to reflector insertion and no unexpected complications of RGL surgery. CONCLUSION: In our practice, RGL is a safe and effective surgical localization method for soft tissue and nodal melanoma metastases. The inert nature of the reflector enables implantation prior to neoadjuvant therapy with utility in index lymph node removal.

There are a variety of tools available to localize melanoma that had spread to deep layers of the skin or lymph nodes that can guide surgeons to the cancer when the tumor cannot be felt. We evaluated a marker that reflects radar signals that has been studied in breast surgery but not in melanoma. The marker was placed in the tumor before surgery and was located during surgery using a handheld probe, guiding the surgeon to the correct location. An advantage of the radar-reflecting marker we studied is that since it is safe to stay in the body, it can be placed ahead of the use of cancer medications and can keep track of the tumor as it responds to treatment. In a review of 23 surgeries in which the radar-reflecting marker was used, there was one case where the marker migrated away from the tumor and one case where the marker was not able to be located. Monitoring or alternative definitive treatment was provided in each of these cases. Overall, we found the marker to be an effective tumor localization tool for surgeons and safe for patients. Other marker options available are unable or less suitable to be placed a long time in advance of surgery due to either technical or safety reasons, so the radar-reflecting marker is especially useful when it is placed in a tumor ahead of medical treatment leading up to planned surgical treatment.

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation.

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.

Human intervention caused massive destruction of the second largest mangrove forest, Chakaria Sundarbans, Bangladesh.

Mangroves provide essential ecosystem services including coastal protection by acting as coastal greenbelts; however, human-driven anthropogenic activities altered their existence and ecosystem functions worldwide. In this study, the successive degradation of the second largest mangrove forest, Chakaria Sundarbans situated at the northern Bay of Bengal part of Bangladesh was assessed using remote sensing approaches. A total of five multi-temporal Landsat satellite imageries were collected and used to observe the land use land cover (LULC) changes over the time periods for the years 1972, 1990, 2000, 2010, and 2020. Further, the supervised classification technique with the help of support vector machine (SVM) algorithm in ArcGIS 10.8 was used to process images. Our results revealed a drastic change of Chakaria Sundarbans mangrove forest, that the images of 1972 were comprised of mudflat, waterbody, and mangroves, while the images of 1990, 2000, 2010, and 2020 were classified as waterbody, mangrove, saltpan, and shrimp farm. Most importantly, mangrove forest was the largest covering area a total of 64.2% in 1972, but gradually decreased to 12.7%, 6.4%, 1.9%, and 4.6% for the years 1990, 2000, 2010, and 2020, respectively. Interestingly, the rate of mangrove forest area degradation was similar to the net increase of saltpan and shrimp farms. The kappa coefficients of classified images were 0.83, 0.87, 0.80, 0.87, and 0.91 with the overall accuracy of 88.9%, 90%, 85%, 90%, and 93.3% for the years 1972, 1990, 2000, 2010, and 2020, respectively. By analyzing normalized difference vegetation index (NDVI), soil adjusted vegetation index (SAVI), and transformed difference vegetation index (TDVI), our results validated that green vegetated area was decreased alarmingly with time in this study area. This destruction was mainly related to active human-driven anthropogenic activities, particularly creating embankments for fish farms or salt productions, and cutting for collection of wood as well. Together all, our results provide clear evidence of active anthropogenic stress on coastal ecosystem health by altering mangrove forest to saltpan and shrimp farm saying goodbye to the second largest mangrove forest in one of the coastal areas of the Bay of Bengal, Bangladesh.

A case of STING-associated vasculopathy with onset in infancy with novel STING1 variant.

STING-associated vasculopathy with onset in infancy (SAVI) is a rare, monogenic interferonopathy caused by gain-of-function variants in STING1 (TMEM173) characterized by systemic inflammation, cutaneous vasculopathy, and interstitial lung disease. We report a case of SAVI attributed to a novel STING1 p.R284T variant who demonstrated characteristic cutaneous features including telangiectasias, livedo and acrocyanotic changes on face and extremities, as well as saddle nose deformity, failure to thrive, inflammatory arthritis and notable lack of pulmonary disease or autoantibody positivity. Due to the risk for progressive and irreversible lung and tissue damage and evolving therapeutic landscape involving the use of Janus kinase inhibitors, it is critical to recognize variable clinical phenotypes to diagnose and consider treatment options for SAVI patients early in their disease course.

Will trees or grasses profit from changing rainfall regimes in savannas?

Increasing rainfall variability is widely expected under future climate change scenarios. How will savanna trees and grasses be affected by growing season dry spells and altered seasonality and how tightly coupled are tree-grass phenologies with rainfall? We measured tree and grass responses to growing season dry spells and dry season rainfall. We also tested whether the phenologies of 17 deciduous woody species and the Soil Adjusted Vegetation Index of grasses were related to rainfall between 2019 and 2023. Tree and grass growth was significantly reduced during growing season dry spells. Tree growth was strongly related to growing season soil water potentials and limited to the wet season. Grasses can rapidly recover after growing season dry spells and grass evapotranspiration was significantly related to soil water potentials in both the wet and dry seasons. Tree leaf flushing commenced before the rainfall onset date with little subsequent leaf flushing. Grasses grew when moisture became available regardless of season. Our findings suggest that increased dry spell length and frequency in the growing season may slow down tree growth in some savannas, which together with longer growing seasons may allow grasses an advantage over C3 plants that are advantaged by rising CO2 levels.

Single-cell RNA-sequencing of PBMCs from SAVI patients reveals disease-associated monocytes with elevated integrated stress response.

Gain-of-function mutations in stimulator of interferon gene 1 (STING1) result in STING-associated vasculopathy with onset in infancy (SAVI), a severe autoinflammatory disease. Although elevated type I interferon (IFN) production is thought to be the leading cause of the symptoms observed in patients, STING can induce a set of pathways, which have roles in the onset and severity of SAVI and remain to be elucidated. To this end, we performed a multi-omics comparative analysis of peripheral blood mononuclear cells (PBMCs) and plasma from SAVI patients and healthy controls, combined with a dataset of healthy PBMCs treated with IFN-ß. Our data reveal a subset of disease-associated monocyte, expressing elevated CCL3, CCL4, and IL-6, as well as a strong integrated stress response, which we suggest is the result of direct PERK activation by STING. Cell-to-cell communication inference indicates that these monocytes lead to T cell early activation, resulting in their senescence and apoptosis. Last, we propose a transcriptomic signature of STING activation, independent of type I IFN response.

Regulation of STING activity in DNA sensing by ISG15 modification.

Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of HIV-1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses STING-mediated type Ⅰ interferon induction by inhibiting its oligomerization. Of note, removal of STING ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy (SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization. Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents an important regulatory step in DNA sensing of viruses and autoimmune responses.

Case report: JAK1/2 inhibition with baricitinib in the treatment of STING-associated vasculopathy with onset in infancy.

BACKGROUND: Gain-of-function mutations in STING1 (also known as TMEM173) which result in constitutive activation of STING, have been reported to cause STING-associated vasculopathy with onset in infancy (SAVI). Although a wider spectrum of associated manifestations and perturbations in disease onset have been observed since its description, the genotype-phenotype correlations are not definite, and there is no established treatment protocol for SAVI. CASE PRESENTATION: Herein, we report a kindred, heterozygous STING mutation (p.V155M) in which the 2-year-old proband suffered from severe interstitial lung disease (ILD) while her father was initially misdiagnosed with connective tissue disease associated with ILD at an adult age. Baricitinib was initiated after the diagnosis of SAVI in the proband combined with steroids, and during the 14-month follow-up, the respiratory symptoms were improved. However, as the improvement of laboratory indicators was limited, especially in autoimmune indices, and the lung CT images remained unaltered, it seems that JAK1/2 inhibition was unsatisfactory in completely controlling the inflammation of the disease in our study. CONCLUSIONS: Baricitinib was shown to elicit some effect on the ILD but failed to control the inflammation of the disease completely. Further exploration of JAK inhibitors or other therapeutic strategies are needed to more optimally treat this inflammatory disease.

Lung Transplantation under a Janus Kinase Inhibitor in Three Patients with SAVI Syndrome.

Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a very rare autoinflammatory disease related to STING1 mutation. SAVI is mainly characterized by fever attacks and skin and respiratory manifestations such as interstitial lung disease or alveolar hemorrhage. Respiratory involvement occurs in 80% of cases and might progress to severe lung fibrosis and require lung transplantation (LT). Three patients with SAVI who underwent LT have been reported to date. Two of the three patients died months or years after LT due to multiple organ failure or sepsis. However, the diagnosis of SAVI was made after LT, thus preventing the use of targeted therapy, such as the Janus kinase 1 and 2 inhibitor (JAK1/2i) ruxolitinib, which might be beneficial for the respiratory status of these patients. We aimed to report our experience in managing three patients who were followed in three large lung transplantation centers in France and who benefited from ruxolitinib before undergoing LT. We describe posttransplant complications that occurred as well as outcomes.

Isolation and characterisation of secondary metabolites from Trifolium vesiculosum Savi and their antiproliferative activities.

One unreported flavonol namely morin-7-O-methyl ether (1) along with seven known compounds were isolated from the aerial parts of Trifolium vesiculosum Savi which were elucidated by using extensive spectroscopic methods such as 1D and 2D NMR and HR-MS. According to the cell viability assay (MTS) on the purified compounds (1-8), quercetin-3-O-(6''-trans-p-coumaroyl)-ß-galactoside (4) revealed remarkable antiproliferative activity most particularly against breast cancer cells (IC50 = 2.90 ± 0.25 µM in HCC1937 and 7.98 ± 0.57 µM in MCF7) while moderate inhibitory activity (IC50 = 17.96 ± 0.51-51.70 ± 2.69 µM) on prostate, colorectal and liver cancer cell viability was observed. Further mechanistic examinations (Annexin V/PI staining, DNA content and detection of reactive oxygen species analyses) showed that compound 4 significantly induced apoptosis, enhanced mitochondrial reactive oxygen species (ROS) accumulation, and caused cell cycle arrest in cancer cells by increasing accumulation of cells at G0/G1 and/or G2/M phases of the cell cycle.