Cystatin C is glucocorticoid-responsive, directs recruitment of Trem2+ macrophages and predicts failure of cancer immunotherapy (preprint)

Summary Cystatin C (CyC) is a secreted cysteine protease inhibitor and its biological functions remain insufficiently characterized. Plasma CyC is elevated in many patients, especially when receiving glucocorticoid (GC) treatment. Endogenous GCs are essential for life and are appropriately upregulated in response to systemic stress. Here we empirically connect GCs with systemic regulation of CyC. We used genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. CyC production and a polygenic score (PGS) capturing germline predisposition to CyC production predicted elevated all-cause and cancer-specific mortality. We then demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells. Using isogenic CyC-knockout tumors, we discovered a markedly attenuated tumor growth in vivo and found abrogated recruitment of Trem2+ macrophages, which have been previously linked to failure of cancer immunotherapy. Finally, we showed that the CyC-production PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients. Taken together, our results demonstrate that CyC may be a direct effector of GC-induced immunosuppression, acting through recruitment of Trem2+ macrophages, and therefore could be a target for combination cancer immunotherapy.

Design and Control of a Highly Redundant Rigid-Flexible Coupling Robot to Assist the COVID-19 Oropharyngeal-Swab Sampling (preprint)

The outbreak of novel coronavirus pneumonia (COVID-19) has caused mortality and morbidity worldwide. Oropharyngeal-swab (OP-swab) sampling is widely used for the diagnosis of COVID-19 in the world. To avoid the clinical staff from being affected by the virus, we developed a 9-degree-of-freedom (DOF) rigid-flexible coupling (RFC) robot to assist the COVID-19 OP-swab sampling. This robot is composed of a visual system, UR5 robot arm, micro-pneumatic actuator and force-sensing system. The robot is expected to reduce risk and free up the clinical staff from the long-term repetitive sampling work. Compared with a rigid sampling robot, the developed force-sensing RFC robot can facilitate OP-swab sampling procedures in a safer and softer way. In addition, a varying-parameter zeroing neural network-based optimization method is also proposed for motion planning of the 9-DOF redundant manipulator. The developed robot system is validated by OP-swab sampling on both oral cavity phantoms and volunteers.

Traditional Chinese medicine syndrome differentiation of coronavirus disease 2019 patients

Objective To explore the rule of traditional Chinese medicine (TCM) syndrome differentiation of coronavirus disease 2019 (COVID-19) patients. Methods The symptoms of 756 cases with COVID-19 in Guanggu Branch of Maternity and Child Healthcare Hospital of Hubei Province were collected by cross sectional survey. The incidence rates of the symptoms were recorded by frequency method at different courses of the disease: prodromal stage (onset), middle stage (7-30 days), and later stage (>30 days). The common symptoms (incidence rate>5.0%) were analyzed by systematic clustering. With expert experience, the rule of TCM syndrome differentiation of COVID-19 patients was summarized. Results Fever (52.25%, 395 cases), cough (43.25%, 327 cases), asthenia (27.25%, 206 cases), chest distress (26.72%, 202 cases), asthma (17.59%, 133 cases) and expectoration (5.03%, 38 cases) were the most common symptoms in the prodromal stage (756 cases) of the disease, which were clustered into one category except expectoration, indicating the pathogenesis of both lung and body surface suppressed by dampness. In the middle stage (383 cases), the 19 common symptoms including greasy fur (64.49%, 247 cases), yellow fur (43.86%, 168 cases), thick fur (40.21%, 154 cases), cough (34.73%, 133 cases), red tongue (32.38%, 124 cases), poor stool (25.85%, 99 cases), asthma (25.33%, 97 cases), asthenia (25.07%, 96 cases), poor appetite (23.76%, 91 cases), bitterness of mouth (14.36%, 55 cases), dry fur (12.01%, 46 cases), purple tongue (12.01%, 46 cases), perspiration (11.49%, 44 cases), constipation (10.18%, 39 cases), white phlegm (8.62%, 33 cases), insomnia (7.31%, 28 cases), nausea (7.05%, 27 cases), diarrhea (6.79%, 26 cases) and yellow phlegm (6.27%, 24 cases), were clustered into three groups, indicating the pathogenesis of damp-heat accumulation, obstruction of lung and spleen by dampness, and dryness due to dampness-heat. In the later stage (373 cases), the 13 common symptoms including greasy fur (50.94%, 190 cases), asthenia (39.41%, 147 cases), cough (37.80%, 141 cases), red tongue (33.78%, 126 cases), asthma (32.17%, 120 cases), perspiration (23.86%, 89 cases), dry mouth (22.79%, 85 cases), poor appetite (20.11%, 75 cases), poor stool (19.30%, 72 cases), bitterness of mouth (15.01%, 56 cases), white phlegm (10.72%, 40 cases), palpitation (8.31%, 31 cases) and little fur (8.04%, 30 cases), were clustered into two groups, indicating the pathogenesis of deficiency of Qi and Yin with residual dampness, and deficiency of lung Qi and spleen Qi with residual dampness. Conclusion The TCM syndromes of COVID-19 patients in different stages have its own typical characteristics, with a regular change from exterior to interior, from dampness to dampness-heat and from excess to deficiency..