TIM-3 and its interaction with Gal-9 are closely associated with RA disease activity and may play an important role in the pathogenesis of RA. In addition to the negative regulatory effect of Gal-9 mediated through the TIM-3-Gal-9 pathway, Gal-9 may exert its suppressive effect on RA disease activity by modulation of regulatory T (Treg) cells.

In a randomised, controlled, single-blind trial, we examined the effect of a pre-emptive alveolar recruitment strategy on arterial oxygenation during subsequent pneumoperitoneum. After intubation, 50 patients were randomly allocated to receive either tidal volume 10 ml/kg with no positive end-expiratory pressure (group C) or alveolar recruitment strategy of 10 manual breaths with peak inspiratory pressure of 40 cmH2O plus positive end-expiratory pressure of 15 cmH2O before gas insufflation (group P). During pneumoperitoneum, group P was ventilated with the same setting as group C (FiO2=0.35, tidal volume 10 ml/kg). PaO2 measured during peumoperitoneum was higher in group P than in group C (166∓32 mmHg vs 145∓34 mmHg at 15 minutes, P=0.028, 155∓30 mmHg vs 136∓32 mmHg at 30 minutes, P=0.035). Alveolar-arterial oxygen gradient in group P increased less after gas insufflation (13∓9 to 60∓34 mmHg vs 10∓9 to 37∓31 mmHg, P=0.013). We conclude that the alveolar recruitment strategy we applied before insufflation of the peritoneal cavity may improve oxygenation during laparoscopic hysterectomy.

Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.

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These data suggest that the orientation of the J-wire tip downward can increase successful placement rates of right subclavian venous catheterization.