The development of novel point-to-point drugs targeting resistance mechanisms is a critical and popular research field; nevertheless, success remains challenging. Therefore, given the short survival time and heightened expectations of patients with advanced NSCLC, the design of various combination therapy strategies––integrating preclinical, clinical, and real-world evidence (such as radiotherapy, chemotherapy, targeted therapy, antibody–drug conjugates, oncolytic viruses, and cell therapy)––may be a wise and practical choice to address the disease. Resistance to immunotherapy involves almost all cell types in the body, primarily cancer cells and T cells involved in immune surveillance. As a result of space limitations, this article focuses on the progress and challenges of various combined strategies for directly eliminating cancer cells. We also emphasize the realignment of treatment goals, shifting from primarily focusing on eliminating cancer cells (via chemotherapy and radiotherapy) to fully utilizing immune regulation to overcome resistance to immune checkpoint inhibitors.

Objective:To understand the relationship between the RNA shedding time of SARS-CoV-2 infected persons and the single nucleotide mutation of the virus, the population of infected persons, underlying diseases and other factors, so as to provide more clues for the study of SARS-CoV-2 infection dynamics.Methods:The data of epidemiology, clinical manifestations, and underlying diseases of infected persons in a cluster epidemic of COVID-19 in Jiangsu province from July to September 2021 were collected. Nasopharyngeal swab samples of cases were collected, and the whole genome of the virus was sequenced by second-generation sequencing technology. The online analysis platform was used to judge the virus type and analyze the mutation site, and Cox proportional risk model was used to analyze the relationship between the RNA shedding time of SARS-CoV-2 and various research factors.Results:There were 350 persons who finally obtained the whole genome sequence of the virus in this COVID-19 outbreak, of which 60.3% were female, the median age was 49 years old (interquartile range, IQR: 37-65 years old)), and the median time of virus shedding was 33 days ( IQR, 26-44 days). The whole-genome sequencing analysis showed that compared with the Wuhan reference strain sequence, the infected persons’ sequence had 34~41 nucleotide mutation sites, belonging to VOC/Delta variant (B.1.617.2 evolutionary branch), and C346T, C1060T, T2803C, T7513C, A29681C were the main single nucleotide polymorphisms (SNPs) of this epidemic. Cox regression analysis showed that age, underlying disease, clinical classification, vaccination, SNP T2803C and T7513C had an impact on the RNA shedding time of SARS-CoV-2. The adjusted multivariate Cox regression result showed that age [ HR=0.73, 95% CI (0.55, 0.95)] and T7513C [ HR=0.37, 95% CI (0.18, 0.77)] were still the risk factors for the extension of SARS-CoV-2 RNA shedding time. Conclusions:This study analyzed the effects of the individual factors and viral single nucleotide variations on the time of viral RNA shedding. Those who were older, suffered from hypertension, had more severe clinical symptoms, were not vaccinated or incompletely vaccinated, and had T7513C mutation in the infected virus, had a risk of a long RNA shedding time of SARS-CoV-2, which should be given special attention and follow-up after rehabilitation.

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.
Animals ; Coronavirus Papain-Like Proteases/antagonists & inhibitors* ; Cricetinae ; Humans ; Mice ; Pandemics ; SARS-CoV-2/enzymology* ; COVID-19 Drug Treatment

Objective:To investigate the status and correlation of 6 weeks postpartum self-compassion, alexithymia and postpartum depression in preterm mothers separated from their infants.Methods:Convenience sampling method was used to select 300 premature mothers separated from their infants in Binzhou Medical University Hospital as the research objects. A cross-sectional survey was conducted by the general data, the Chinese version of the Self-Compassion Scale (SCS-C), the Chinese version of the Toronto Alexithymia Scale (TAS-20) and the Edinburgh Postnatal Depression Scale (EPDS).Results:The total scores of SCS-C, TAS-20 and EPDS at 6 weeks postpartum were (19.94 ± 2.64), (48.74 ± 3.87) and (10.61 ± 3.07) respectively. The self-compassion ability was negatively correlated with alexithymia and postpartum depression ( r = -0.365, -0.313, both P<0.01), alexithymia was positively correlated with postpartum depression ( r = 0.657, P<0.01). Alexithymia played a partial mediating role in the relationship between self-compassion and postpartum depression, accounting for 72.83% of the total effect. Conclusions:Self-compassion and alexithymia are both important factors affecting postpartum depression in premature mothers separated from their infants. By enhancing emotional cognition and processing ability of premature mothers, self-compassion ability can be improved to reduce the incidence of postpartum depression.

Objective:To investigate the safety and efficacy of nimotuzumab combined with IMRT radiotherapy in the treatment of elderly patients with locally advanced cervical cancer (LACC).Methods:A retrospective analysis was conducted for 34 elderly LACC patients treated with nimotuzumab combined with IMRT radiotherapy or concurrent chemoradiotherapy in the Zhangzhou Affiliated Hospital of Fujian Medical University from June 2020 to December 2021. The efficacy and side effects were evaluated one and two years after treatment.Results:Median follow-up time was 13.3 months (6.1-24.3 months). A total of 24 cases of complete response (CR) and eight cases of partial response (PR) were achieved after treatment, with an objective response rate (ORR) of 94.1% (32/34). The tumor diameters were (49.56 ± 19.22) mm before treatment and (19.61 ± 14.59) mm after treatment, with a tumor regression rate (TRR) of 59.22%.The 1- and 2- year progression-free survival (PFS) rates were 84.9% and 84.9%, overall survival (OS) rates 91.8% and 87.2%, respectively, disease-free survival (DFS) rates 91.8% and 87.2%, respectively, and the cancer-specific survival (CSS) rates 95.7% and 90.9%, respectively. The main adverse events included radiation enteritis, leukopenia, hypoproteinemia and anemia.Conclusions:Nimotuzumab combined with IMRT radiotherapy or concurrent chemoradiotherapy is safe and effective in the treatment of LACC.

Humans ; Air Pollutants ; Sleep Apnea, Obstructive ; Polysomnography ; Sleep ; Pulmonary Disease, Chronic Obstructive

Objective:The epidemiological characteristics of PICU deaths in 2017 in the Affiliated Hospital of Guizhou Medical University, Guizhou Provincial People′s Hospital, and Guiyang Children′s Hospital were summarized and analyzed to provide a basis for formulating intervention measures to effectively reduce the mortality rate of children.Methods:The clinical datas of PICU deaths in three tertiary hospitals in 2017 were collected retrospectively.The cases were divided according to different ages and lengths of hospitalization.And gender, age, length of death, length of hospitalization, and death diseases were summarized and analyzed.Results:In 2017, the PICU of the three tertiary hospitals admitted 2 092 children, of which 139 (6.64%) died, including 84 males and 55 females.The months with the highest case fatality rates were January, February, July and August.The fatality rates were 9.14% (18/197), 9.04% (15/166), 13.25% (20/151), 7.93% (13/164), respectively.There was statistically significant difference in the mortality of children admitted in each month ( P=0.038). Among the death cases, the infant group (29 days to 1 year old) accounted for the largest proportion with 58 cases (41.73%), followed by the preschool group (3 to 7 years old) with 37 cases (26.62%), the infant group (1 to 3 years old) with 24 cases(17.27%), and the school-age group (7 to 14 years old) with 20 cases(14.38%). The top three death diseases were: 39 cases (28.06%) of bronchial pneumonia (severe), 28 cases (20.14%) of hematological tumors and solid tumors, and 23 cases (16.55%) of trauma.The difference of its distribution in different age groups was statistically significant( P<0.05). The patients were divided into four groups according to the length of hospital stay.The time ≤1 d group had the highest mortality of 54 cases (38.85%), -3 d group and -7 d group both had 32 cases (23.02%), the >7 d group had the lowest mortality of 21 cases (15.11%). Conclusion:In 2017, January, February and July, August are the peak months of deaths in PICUs in Guizhou, with the highest number of infant deaths.Bronchial pneumonia(severe), hematological tumors and solid tumors, and trauma are the top three death diseases.

Hemodynamic instability is one of the main causes of death in critically ill children.Real-time and dynamic monitoring of hemodynamic changes is an important part of the work in intensive care units and operating rooms.For the past 50 years, invasive pulmonary catheter thermal dilution has been recognized as the "gold standard" for hemodynamic monitoring, but its clinical use has declined in recent years due to its patient injury, complications, and difficulty in operation.Therefore, hemodynamic monitoring techniques that are minimally or completely noninvasive, simple to perform, and highly correlated in accuracy with invasive methods are receiving increasing attention from pediatric clinicians.This review summarized the measuring principle and application status of various monitoring technologies, in order to provide evidence for the selection of appropriate monitoring methods in clinical practice.

Objective:To evaluate the clinical effect of Limb dysfunction after the comprehensive treatment of ischemic stroke by Traditional Chinese Medicine (TCM).Methods:A total of 160 patients with limb dysfunction after ischemic stroke. Who in line with the inclusion criteria, were randomly divided into 2 groups by random number table, 80 cases each. These patients were treated in Multicenter Union Hospital from June 2017 to Janunry 2019. The patients in the control group were given basic Western medicine treatment and rehabilitation training, while the patients in the observation group were given a comprehensive treatment combined with traditional Chinese medicine based on the control group (Chinese herbs, herbal fumigation and ear point press). Both groups were treated for 4 weeks and follow-up for 2 months. The Fugl-Meyerscale were used to evaluate the degree of limb dysfunction and balance dysfunction, the National Institutes of Health Stroke Scale were used for assessing the damage extent of nerve function, the Barthel index for evaluating the mobility of daily life. The clinical efficacy was evaluated according to the method of Brunnstrom assessment.Results:After treatment, the Limb strong spasm (1.57 ± 0.36 vs. 1.98 ± 0.53, t=5.724), Hemianesthesia (1.37 ± 0.31 vs. 1.80 ± 0.36, t=8.096), Inhibited bending and stretching (1.31 ± 0.25 vs. 1.84 ± 0.46, t=9.055) in the observation group were significantly lower than those in the control group ( P<0.01). The Fugl-Meyer activity and balance rating in the observation group were significantly higher than those in the control group ( t values were 2.739, 4.705, respectively, P<0.05 or P<0.01). The total effective rate of observation group was 93.3% (78/80), the control group was 73.3% (71/80), and there exist statistical significance ( χ2=4.783, P=0.028) in the two group’s comparative difference. Conclusion:The comprehensive TCM treatment can improve the hemiplegia syndrome of ischemic stroke patients and their limb activity and balance function, promote their neural functional recovery, enhance the activity of their daily life and clinical efficacy.

Objective:To observe the clinical effect of Shufeng Xuanfei Zhike decoction on cough variant asthma.Methods:A total of 86 patients with cough variant asthma admitted to the Second People's Hospital of Yuyao from August 2016 to July 2017 were selected and divided into two groups according to the random digital table method, with 43 cases in each group.The control group was given conventional treatment, and the observation group was given Shufeng Xuanfei Zhike decoction combined with conventional treatment.The clinical efficacy, symptom score, inflammatory factors and adverse reactions were observed.Results:The total effective rate of the observation group was 95.35%(41/43), which was higher than 79.07%(34/43) of the control group, the difference was statistically significant(χ 2=5.108, P=0.024). The symptom scores of cough[(1.23±0.56)points], sputum[(0.66±0.27)points], nasal congestion[(0.64±0.30)points], shortness of breath[(0.55±0.18)points] and pharyngeal itch[(0.70±0.24)points] in the observation group were lower than those in the control group[(2.73±0.85)points, (1.18±0.52)point, (1.18±0.45)point, (1.02±0.47)points, (1.38±0.58)points], the differences were statistically significant( t=9.663, 5.820, 6.547, 6.124, 7.104, all P<0.05). After treatment, the levels of interleukin 4, interleukin 6, hypersensitive C-reactive protein and tumor necrosis factor alpha in the observation group were (5.26±1.68)ng/L, (8.35±1.00)ng/L, (2.08±0.21)mg/L, (0.75±0.22)ng/L, respectively, which were lower than those in the control group[(8.73±1.77)ng/L, (12.30±1.24)ng/L, (4.33±0.38)mg/L, (1.75±0.34)ng/L], and the differences were statistically significant( t=9.324, 16.260, 33.983, 16.192, all P<0.05). The level of interleukin 10 in the observation group [(29.94±8.88)ng/L] was higher than that in the control group[(22.66±8.37)ng/L]( t=3.912, P<0.05). No obvious adverse reactions were observed in both two groups. Conclusion:Shufeng Xuanfei Zhike decoction is safe and effective in the treatment of patients with cough variant asthma.