PD-L1 overexpression induces STAT signaling and promotes the secretion of pro-angiogenic cytokines in non-small cell lung cancer (NSCLC).

BACKGROUND: Monoclonal antibodies (ICI) targeting the immune checkpoint PD-1/PD-L1 alone or in combination with chemotherapy have demonstrated relevant benefits and established new standards of care in first-line treatment for advanced non-oncogene addicted non-small cell lung cancer (NSCLC). However, a relevant percentage of NSCLC patients, even with high PD-L1 expression, did not respond to ICI, highlighting the presence of intracellular resistance mechanisms that could be dependent on high PD-L1 levels. The intracellular signaling induced by PD-L1 in tumor cells and their correlation with angiogenic signaling pathways are not yet fully elucidated. METHODS: The intrinsic role of PD-L1 was initially checked in two PD-L1 overexpressing NSCLC cells by transcriptome profile and kinase array. The correlation of PD-L1 with VEGF, PECAM-1, and angiogenesis was evaluated in a cohort of advanced NSCLC patients. The secreted cytokines involved in tumor angiogenesis were assessed by Luminex assay and their effect on Huvec migration by a non-contact co-culture system. RESULTS: PD-L1 overexpressing cells modulated pathways involved in tumor inflammation and JAK-STAT signaling. In NSCLC patients, PD-L1 expression was correlated with high tumor intra-vasculature. When challenged with PBMC, PD-L1 overexpressing cells produced higher levels of pro-angiogenic factors compared to parental cells, as a consequence of STAT signaling activation. This increased production of cytokines involved in tumor angiogenesis largely stimulated Huvec migration. Finally, the addition of the anti-antiangiogenic agent nintedanib significantly reduced the spread of Huvec cells when exposed to high levels of pro-angiogenic factors. CONCLUSIONS: In this study, we reported that high PD-L1 modulates STAT signaling in the presence of PBMC and induces pro-angiogenic factor secretion. This could enforce the role of PD-L1 as a crucial regulator of the tumor microenvironment stimulating tumor progression, both as an inhibitor of T-cell activity and as a promoter of tumor angiogenesis.

Hypoxemia and arterial hypotension at the accident scene in head injury.

OBJECTIVE: To quantify the occurrence of arterial hypotension and arterial oxygen desaturation in a series of patients with head trauma rescued by helicopter. DESIGN: Prospective, observational study. MATERIALS AND METHODS: Arterial HbO2 was measured before tracheal intubation at the accident scene in 49 consecutive patients with head injuries. Arterial pressure was measured using a sphygmomanometer. MAIN RESULTS: Mean arterial saturation was 81% (SD 24.24); mean arterial systolic pressure was 112 mm Hg (SD 37.25). Airway obstruction was detected in 22 cases. Twenty-seven patients showed an arterial saturation lower than 90% on the scene, and 12 had a systolic arterial pressure of less than 100 mm Hg. The outcome was significantly worse in cases of hypotension, desaturation, or both. CONCLUSIONS: Hypoxemia and shock are frequent findings on patients at the accident scene. Hypoxemia is more frequently detected and promptly corrected, white arterial hypotension is more difficult to control. Both insults may have a significant impact on outcome.

[Anesthesiologic management in scleroderma patients. Presentation of a clinical case]. / Condotta anestesiologica nel paziente sclerodermico. Presentazione di un caso clinico.

The scleroderma (literally, hard skin), or progressive systemic sclerosis (PSS), is a multisystem disease and can present various anaesthetic problems. The anaesthesist should be aware of the difficulty in opening mouth wide enough for laryngoscopy and intubation, the possibility that cardiopulmonary changes may be present and the probability of lesions in oesophagus, bowel, kidneys, skin and joints. In this article the authors describe the anesthetic management of a patient with Thibierge-Weissenbach syndrome (scleroderma with calcinosis cutis) and explore potential problems that should be anticipated by the anesthesiologist.

Field potentials evoked in the subiculum following postsynaptic discharge of hippocampal pyramidal neurons.

Evoked potentials, represented by population spikes and slow waves, have been recorded from the subiculum, along its whole dorso-ventral extent, following postsynaptic activation and discharge of hippocampal pyramidal neurons. These potentials can be associated with synaptic excitatory effects generated on radially oriented neurons by hippocampal impulses reaching the subiculum at any dorso-ventral level, according to a segmental organization.

Selective activation of field CA1-CA2 by perforant neurons discharging in response to hippocampal efferent volleys.

A long lasting evoked response, generated in the hippocampal field CA1-CA2 following postsynaptic sequential discharge of hippocampal pyramids and entorhinal neurons, has been analyzed by multiple simultaneous surface and depth recordings in the guinea pig dorsal hippocampal region. Results obtained suggest that it can be associated with postsynaptic excitatory potentials evoked in the distal portion of the apical dendrites of field CA1-CA2 pyramids by perforant neurons selectively discharged by impulses of hippocampal origin.