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For the advancements of photoresponsive materials with tunable properties, the usage of multidimensional signals is desired. Using the polarization of the light in addition to the wavelength represents a further parameter to control the materials properties. Here, the first‐time dynamic and reversible manipulation of the guest‐host properties of a nanoporous material by linearly polarized light (LPL) is reported. The material is based on a metal–organic framework (MOF) with photoresponsive azobenzene side groups covalently connected to the MOF structure. The azobenzene moieties are reversibly reoriented by LPL, making the MOF structure and, thus, the pores anisotropic. As a result, the mobility of the guest molecules in the pores of the initially isotropic material becomes anisotropic, which can be dynamically controlled by the light polarization. The experiments by impedance spectroscopy are supported by molecular dynamics (MD) simulations. The study shows that the light polarization can be a further parameter to modify the material properties, allowing a more complex and more refined level of control for smart materials. The polarization of light is introduced as a further parameter to dynamically and reversibly control the properties of a photoresponsive nanoporous material. It was used to control the mobility of the guest molecules in the pores of a metal–organic framework. The metal–organic framework contains azobenzene side groups which are reoriented by linearly polarized light, creating anisotropic pores.

Due to their similar boiling points, separation of benzene and cyclohexane mixtures is among the current challenging processes faced by the petrochemical industry. As recently assessed, the soft imine‐based covalent organic framework [(TAM)(BDA)2] (COF‐300; TAM = tetrakis(4‐aminophenyl)methane, BDA = terephthaldehyde) possesses higher affinity for benzene than cyclohexane in both static conditions at 298 K and dynamic conditions in the range of 298–348 K. As shown in this contribution, in situ powder X‐ray diffraction while dosing benzene and cyclohexane vapors in the range of 0.01–4.74 bar on the narrow‐pore form of COF‐300 confirmed the coherent switchability of its framework, unveiling the progressive formation of different intermediate‐ and large‐pore forms. In addition, a basket of otherwise inaccessible key crystallochemical details—“on/off” structural‐feature changes cooperating to adsorption, primary adsorption sites, and host–guest and guest–guest interactions—was successfully retrieved. Overall, these findings allowed to shed light on the framework dynamics underneath the previously observed selectivity toward benzene over cyclohexane, completing this case of study and providing relevant information for the design of new‐generation adsorbents for this applicative context. In situ powder X‐ray diffraction confirms the switchability of the covalent organic framework (COF)‐300 during benzene and cyclohexane adsorption. Starting from the narrow‐pore form, intermediate‐ and large‐pore forms, as well as structural changes and host ‐guest interactions favoring adsorption, are identified. Disclosing the framework dynamics underneath COF‐300 selectivity toward benzene provides key information for new‐generation adsorbents in this applicative context.

In Extreme Southern dialects of Italy, complement clauses can appear in three different ways: (1) with the infinitive; (2) with mŏdo + ind. (in Salentino quod + ind.); (3) with ca/chi + ind. Dependent finite clauses headed by mŏdo/quod replace the infinitive particularly when the matrix predicate is a verb expressing will, wish, aim or intention. This replacement, which represents a syntactic calque from Italo-Greek varieties, finished to involve also the verb potere 'can', in a different way from Italo-Greek, where it is is the only verbal form which never appears in this construction. Aim of this paper is twofold: (1) showing the contexts where potere surfaces with a dependent clause; (2) trying to clarify why verbs expressing will or wish constitute the core of predicates which occur with mŏdo/quod + ind.

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on its survival and mitogenic effects towards endothelial cells, with moderate so far success of anti-angiogenic therapy. However, VEGF can have multiple effects on additional cell types including immune and tumor cells, by directly influencing and promoting tumor cell survival, proliferation and invasion and contributing to an immunosuppressive microenvironment. In this review, we summarize the effects of the VEGF/VEGFR pathway on non-endothelial cells and the resulting implications of anti-angiogenic agents that include direct inhibition of tumor cell growth and immunostimulatory functions. Finally, we present how previously unappreciated studies on VEGF biology, that have demonstrated immunomodulatory properties and tumor regression by disrupting the VEGF/VEGFR pathway, now provide the scientific basis for new combinational treatments of immunotherapy with anti-angiogenic agents.

B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10 + Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10 + Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10 + Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10 + Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases. Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10 + Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.

Acute respiratory distress syndrome (ARDS) remains an important clinical challenge with a mortality rate of 35–45%. It is being increasingly demonstrated that the improvement of outcomes requires a tailored, individualized approach to therapy, guided by a detailed understanding of each patient’s pathophysiology. In patients with ARDS, disturbances in the physiological matching of alveolar ventilation (V) and pulmonary perfusion (Q) (V/Q mismatch) are a hallmark derangement. The perfusion of collapsed or consolidated lung units gives rise to intrapulmonary shunting and arterial hypoxemia, whereas the ventilation of non-perfused lung zones increases physiological dead-space, which potentially necessitates increased ventilation to avoid hypercapnia. Beyond its impact on gas exchange, V/Q mismatch is a predictor of adverse outcomes in patients with ARDS; more recently, its role in ventilation-induced lung injury and worsening lung edema has been described. Innovations in bedside imaging technologies such as electrical impedance tomography readily allow clinicians to determine the regional distributions of V and Q, as well as the adequacy of their matching, providing new insights into the phenotyping, prognostication, and clinical management of patients with ARDS. The purpose of this review is to discuss the pathophysiology, identification, consequences, and treatment of V/Q mismatch in the setting of ARDS, employing experimental data from clinical and preclinical studies as support.

Study designProspective cohort study.ObjectivesTo determine the incidence and evaluate the characteristics of newly injured patients admitted to two spinal cord injury (SCI) centers during a 4-year period.SettingOulu and Tampere University Hospital, Finland.MethodsA dedicated multidisciplinary team evaluated all of the patients with new traumatic SCI (TSCI). The data were recorded according to the International Spinal Cord Injury Core Data Sets.ResultsIn a 4-year period, 346 new patients with TSCI were admitted to the study centers. In the Oulu and Tampere University Hospitals’ catchment areas, the mean annual incidence of TSCI was 36.6 per million. The leading causes of injury were low-level falls (36.2%), high-level falls (25.5%), and transport-related accidents (19.2%). In the patients >60 years, 72.6% were injured by falling and the proportion of low-level falls was 49.7%. In the patients ≤60 years old, 47.4% were alcohol-related. The proportion of cervical injuries in the patients >60 years was 77.1%, while in the patients ≤60 years the proportion was 59.6%. The incidence of TSCI was higher during the Summer and Autumn months.ConclusionThe mean annual incidence of TSCI was 36.6 per million corresponding to 200 new annual cases in Finland. Incomplete tetraplegia due to falling among elderly was overrepresented in the study population. Alcohol-consumption preceded injury in nearly half of the cases in the younger population. The prevention should focus on alcohol-related injuries and falls in the elderly.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC), but the emergence of resistance mutations restricts their efficacy. We previously showed that RAS , BRAF and EGFR mutant alleles, which appear in circulating tumor DNA (ctDNA) during EGFR blockade, decline upon therapy withdrawal. We hypothesized that monitoring resistance mutations in blood could rationally guide subsequent therapy with anti-EGFR antibodies. We report here the results of CHRONOS, an open-label, single-arm phase 2 clinical trial exploiting blood-based identification of RAS / BRAF / EGFR mutations levels to tailor a chemotherapy-free anti-EGFR rechallenge with panitumumab (ClinicalTrials.gov: NCT03227926 ; EudraCT 2016-002597-12). The primary endpoint was objective response rate. Secondary endpoints were progression-free survival, overall survival, safety and tolerability of this strategy. In CHRONOS, patients with tissue- RAS WT tumors after a previous treatment with anti-EGFR-based regimens underwent an interventional ctDNA-based screening. Of 52 patients, 16 (31%) carried at least one mutation conferring resistance to anti-EGFR therapy and were excluded. The primary endpoint of the trial was met; and, of 27 enrolled patients, eight (30%) achieved partial response and 17 (63%) disease control, including two unconfirmed responses. These clinical results favorably compare with standard third-line treatments and show that interventional liquid biopsies can be effectively and safely exploited in a timely manner to guide anti-EGFR rechallenge therapy with panitumumab in patients with mCRC. Further larger and randomized trials are warranted to formally compare panitumumab rechallenge with standard-of-care therapies in this patient setting. In a phase 2 trial, monitoring tumor resistance mutations in blood using liquid biopsies allowed rationally guided subsequent therapy with anti-EGFR antibodies in patients with colorectal cancer.

PurposeThere are conflicting results on the potential role of HER2-status on the efficacy of aromatase inhibitors (AIs) and tamoxifen (TAM) in patients with hormone receptor (HR)-positive breast cancer (BC). The purpose of this population-based cohort study was to investigate the potential benefit of AIs compared to TAM as adjuvant therapy in postmenopausal BC patients by HER2-status in the era of modern therapy with HER2-blockade.MethodsA population-based cohort study was performed including all postmenopausal women diagnosed with HR-positive BC without distant metastasis between 2007 and 2012 in three healthcare regions in Sweden. We analyzed the breast cancer-specific survival (BCSS) and overall survival (OS) in two distinct cohorts (HER2-negative, HER2-positive) based on the type of endocrine therapy (ET) used. A propensity score matching was performed separately in the HER2-negative and HER2-positive cohorts, respectively.ResultsAfter propensity score matching, 4368 patients with HER2-negative and 214 patients with HER2-positive BC were available for analysis. In the HER2-negative cohort, an improved BCSS [Hazard Ratio (HR): 0.51; 95% confidence interval (CI): 0.34–0.77, p value < 0.001] and a trend toward improved OS (HR: 0.66; 95% CI: 0.41–1.08, p value = 0.093) in favor of AI-based therapy was observed. In the HER2-positive cohort, no statistically significant difference between AI-based ET and TAM was found in terms of either BCSS or OS, although the direction of HR was similar as in the HER2-negative cohort (HR for BCSS: 0.84; 95% CI: 0.14–5.04, p = 0.849; HR for OS: 0.62; 95% CI: 0.10–3.38, p = 0.345).ConclusionOur study results, based on propensity-matched cohorts, did not support any predictive value of HER2-status on endocrine therapy in postmenopausal BC patients. AI-based ET remains the treatment of choice for postmenopausal BC patients with HR-positive disease in the modern era of HER2-directed therapy irrespective of HER2-status.

IntroductionBrain metastases from solid tumours are the most common intracranial neoplasms and significantly impact patients’ quality of life and overall survival (OS). Despite advances in oncological therapies, these patients have often been excluded from clinical trials, limiting our understanding of the efficacy of new treatments, such as immunotherapy, in this population. Investigating the tumour microenvironment (TME) of brain metastases is challenging, particularly in determining whether immunotherapy is effective for these lesions. The aim of this study is to investigate the host’s immune response to primary tumours and concomitant brain metastases in the central nervous system from various malignancies.Material and methodsA retrospective study was conducted to examine tumour-infiltrating lymphocytes (TIL) and the expression of programmed cell death 1 and programmed death ligand 1 (PD-L1) in tissue samples from 72 patients with predominant solid tumours and synchronous or metachronous brain metastases. Correlations with different parameters were analysed to evaluate the prognosis of these patients.ResultsAll metastatic tumour samples exhibited decreased intraepithelial CD3 and CD8 levels compared to primary tumours, with variable FOXP3 levels and no consistent difference in PD-L1 levels in tumour cells. Programmed death ligand 1 expression in immune cells was generally lower in metastatic lesions compared to primary tumours. The median OS from diagnosis (OS1) was 19.1 months (95% CI: 13.6–35.1), and the median OS from the diagnosis of brain metastases (OS2) was 11.35 months.ConclusionsThe brain TME demonstrates varying levels of TIL and immune checkpoint expression, highlighting the need for further research to develop effective therapies for intracranial metastases.