There are currently few treatment options for pulmonary fibrosis. Innovations may come from a better understanding of the cellular origin of the characteristic fibrotic lesions. We have analyzed ...normal and fibrotic mouse and human lungs by confocal microscopy to define stromal cell populations with respect to several commonly used markers. In both species, we observed unexpected heterogeneity of stromal cells. These include numerous cells with molecular and morphological characteristics of pericytes, implicated as a source of myofibroblasts in other fibrotic tissues. We used mouse genetic tools to follow the fates of specific cell types in the bleomcyin-induced model of pulmonary fibrosis. Using inducible transgenic alleles to lineage trace pericyte-like cells in the alveolar interstitium, we show that this population proliferates in fibrotic regions. However, neither these cells nor their descendants express high levels of the myofibroblast marker alpha smooth muscle actin (Acta2, aSMA). We then used a Surfactant protein C-CreER T2 knock-in allele to follow the fate of Type II alveolar cells (AEC2) in vivo. We find no evidence at the cellular or molecular level for epithelial to mesenchymal transition of labeled cells into myofibroblasts. Rather, bleomycin accelerates the previously reported conversion of AEC2 into AEC1 cells. Similarly, epithelial cells labeled with our Scgb1a1-CreER allele do not give rise to fibroblasts but generate both AEC2 and AEC1 cells in response to bleomycin-induced lung injury. Taken together, our results show a previously unappreciated heterogeneity of cell types proliferating in fibrotic lesions and exclude pericytes and two epithelial cell populations as the origin of myofibroblasts.
We present a family of trigonal pyramidal iron(II) complexes supported by tris(pyrrolyl-α-methyl)amine ligands of the general formula M(solv) n (tpaR)Fe (M = Na, R = tert-butyl (1), phenyl (4); M = ...K, R = mesityl (2), 2,4,6-triisopropylphenyl (3), 2,6-difluorophenyl (5)) and their characterization by X-ray crystallography, Mössbauer spectroscopy, and high-field EPR spectroscopy. Expanding on the discovery of slow magnetic relaxation in the recently reported mesityl derivative 2, this homologous series of high-spin iron(II) complexes enables an initial probe of how the ligand field influences the static and dynamic magnetic behavior. Magnetization experiments reveal large, uniaxial zero-field splitting parameters of D = −48, −44, −30, −26, and −6.2 cm−1 for 1−5, respectively, demonstrating that the strength of axial magnetic anisotropy scales with increasing ligand field strength at the iron(II) center. In the case of 2,6-difluorophenyl substituted 5, high-field EPR experiments provide an independent determination of the zero-field splitting parameter (D = −4.397(9) cm−1) that is in reasonable agreement with that obtained from fits to magnetization data. Ac magnetic susceptibility measurements indicate field-dependent, thermally activated spin reversal barriers in complexes 1, 2, and 4 of U eff = 65, 42, and 25 cm−1, respectively, with the barrier of 1 constituting the highest relaxation barrier yet observed for a mononuclear transition metal complex. In addition, in the case of 1, the large range of temperatures in which slow relaxation is observed has enabled us to fit the entire Arrhenius curve simultaneously to three distinct relaxation processes. Finally, zero-field Mössbauer spectra collected for 1 and 4 also reveal the presence of slow magnetic relaxation, with two independent relaxation barriers in 4 corresponding to the barrier obtained from ac susceptibility data and to the 3D energy gap between the M S = ±2 and ±1 levels, respectively.
Slow magnetic relaxation is observed for (tpaMes)Fe−, a trigonal pyramidal complex of high-spin iron(II), providing the first example of a mononuclear transition metal complex that behaves as a ...single-molecule magnet. Dc magnetic susceptibility and magnetization measurements reveal a strong uniaxial magnetic anisotropy (D = −39.6 cm−1) acting on the S = 2 ground state of the molecule. Ac magnetic susceptibility measurements indicate the absence of slow relaxation under zero applied dc field as a result of quantum tunneling of the magnetization. Application of a 1500 Oe dc field initiates slow magnetic relaxation, which follows a thermally activated tunneling mechanism at high temperature to give an effective spin-reversal barrier of U eff = 42 cm−1 and follows a temperature-independent tunneling mechanism at low temperature. In addition, the magnetic relaxation time shows a pronounced dc-field dependence, with a maximum occurring at ∼1500 Oe.
Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug ...conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).
Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.
Of the 55 patients, 51% had received ≥2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab + doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% 95% confidence interval (CI): 13%-37%. Median duration of response (DOR) was 4.2 months (range: 1.0
-9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%-43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%-35%), median DOR of 6.0 months (range: 1.0
-9.7), and 6-month PFS rate of 40% (95% CI: 24%-55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.
Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.
Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue ...factor-directed antibody–drug conjugate, in this patient population.
This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396.
102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 38% of 101 patients), epistaxis (30 30%), nausea (27 27%), conjunctivitis (26 26%), fatigue (26 26%), and dry eye (23 23%). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three 3% patients), fatigue (two 2%), ulcerative keratitis (two 2%), and peripheral neuropathies (two 2% each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two 2% patients) and pyrexia (two 2%). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes.
Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer.
Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.
The use of radical bridging ligands to facilitate strong magnetic exchange between paramagnetic metal centers represents a key step toward the realization of single-molecule magnets with high ...operating temperatures. Moreover, bridging ligands that allow the incorporation of high-anisotropy metal ions are particularly advantageous. Toward these ends, we report the synthesis and detailed characterization of the dinuclear hydroquinone-bridged complexes (Me
tren)
M
(C
H
O
)
(Me
tren = tris(2-dimethylaminoethyl)amine; M = Fe, Co, Ni) and their one-electron-oxidized, semiquinone-bridged analogues (Me
tren)
M
(C
H
O
˙)
. Single-crystal X-ray diffraction shows that the Me
tren ligand restrains the metal centers in a trigonal bipyramidal geometry, and coordination of the bridging hydro- or semiquinone ligand results in a parallel alignment of the three-fold axes. We quantify the
-benzosemiquinone-transition metal magnetic exchange coupling for the first time and find that the nickel(ii) complex exhibits a substantial
< -600 cm
, resulting in a well-isolated
= 3/2 ground state even as high as 300 K. The iron and cobalt complexes feature metal-semiquinone exchange constants of
= -144(1) and -252(2) cm
, respectively, which are substantially larger in magnitude than those reported for related bis(bidentate) semiquinoid complexes. Finally, the semiquinone-bridged cobalt and nickel complexes exhibit field-induced slow magnetic relaxation, with relaxation barriers of
= 22 and 46 cm
, respectively. Remarkably, the Orbach relaxation observed for the Ni complex is in stark contrast to the fast processes that dominate relaxation in related mononuclear Ni
complexes, thus demonstrating that strong magnetic coupling can engender slow magnetic relaxation.
IntroductionDespite progress in adoption of smoke-free policies, smoking in casinos is allowed in some US states, including Nevada. In 2020, for the first time, a resort-style casino in Las Vegas ...prohibited smoking voluntarily. This study is the first to assess air quality in this casino and compare results with similar casinos that allow smoking.MethodsA real-time personal aerosol monitor evaluated particulate matter with a diameter <2.5 µm (PM2.5), a surrogate for secondhand smoke (SHS). PM2.5 was measured at eight Las Vegas casinos, including the smoke-free casino. Each casino was visited twice, and PM2.5 was assessed in smoking-permitted gaming areas and areas where smoking is otherwise prohibited.ResultsAverage PM2.5 levels were significantly higher in casinos that allow smoking, for both casino gaming areas and areas where smoking is otherwise prohibited (p<0.05). Mean PM2.5 in gaming areas was 164.9 µg/m3 in casinos that allow smoking and 30.5 µg/m3 in the smoke-free casino. Mean PM2.5 in areas where smoking is otherwise prohibited was 83.2 µg/m3 in casinos which allowed smoking in gaming areas, and 48.1 µg/m3 in the smoke-free casino.ConclusionDespite robust evidence about the harms of SHS, tens of thousands of casino employees and tens of millions of tourists are exposed to high levels of SHS in Las Vegas casinos annually, with PM2.5 levels 5.4 times higher in gaming areas when compared with a smoke-free casino. The only way to protect people from SHS exposure is to prohibit smoking in all indoor areas.
Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 ...Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.
The model compounds (NBu(4))(2)ReCl(4)(CN)(2) (1), (DMF)(4)ZnReCl(4)(CN)(2) (2), and (PY5Me(2))(2)Mn(2)ReCl(4)(CN)(2)(PF(6))(2) (3) have been synthesized to probe the origin of the magnetic ...anisotropy barrier in the one-dimensional coordination solid (DMF)(4)MnReCl(4)(CN)(2) (4). High-field electron paramagnetic resonance spectroscopy reveals the presence of an easy-plane anisotropy (D > 0) with a significant transverse component, E, in compounds 1-3. These findings indicate that the onset of one-dimensional spin correlations within the chain compound 4 leads to a suppression of quantum tunneling of the magnetization within the easy plane, resulting in magnetic bistability and slow relaxation behavior. Within this picture, it is the transverse E term associated with the Re(IV) centers that determines the easy axis and the anisotropy energy scale associated with the relaxation barrier. The results demonstrate for the first time that slow magnetic relaxation can be achieved through optimization of the transverse anisotropy associated with magnetic ions that possess easy-plane anisotropy, thus providing a new direction in the design of single-molecule and single-chain magnets.
Evidence-based interventions (EBIs) for tobacco control can be implemented in worksite settings to reduce tobacco use. Small worksites are less likely to adopt tobacco control EBIs than large ...worksites. The purpose of this qualitative study was to 1) explore factors that impact small employers' decisions to offer tobacco control EBIs, and 2) understand employees' perceptions of tobacco control at small worksites.
Working with staff from small worksites (20-250 employees), we analyzed data from 12 semi-structured interviews with employers (via key informants) and four focus groups with employees. We recruited employers and employees through a purchased business list and market research company, respectively. Interview and focus group topics included perceptions of worksite tobacco control; internal and external forces shaping worksite tobacco control implementation; and perceived worksite support for cessation. We conducted thematic data analysis.
Key themes from the employer interviews included: the local environment played an important role in implementation of tobacco control EBIs; tobacco control was perceived as important but not a priority; and tobacco control decisions were driven by worksite culture. Key themes from the employee focus groups included: perceived employer support for tobacco cessation was limited although there was interest from employees; employees who currently used tobacco were stigmatized for their behavior; and incentives and coaching were considered ideal tobacco control EBIs.
Tobacco control has not been prioritized at small worksites, despite employees welcoming additional cessation support. This study contributes important information on contextual factors and employee preferences that could be targeted to improve tobacco control EBI implementation. Worksites should implement comprehensive tobacco-free policies, minimize stigma when promoting cessation, establish equitable break policies, and involve employees in decision-making related to tobacco control.
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