With the continuous in-depth research on the mechanism of KRAS G12C mutations in targeted therapy of non-small cell lung cancer, KRAS G12C has evolved from non producible to an important targeted therapy site. The KRAS G12C mutation inhibitor has achieved dual progress in efficiency and survival in targeted therapy of non-small cell lung cancer. Although drug resistance is inevitable with treatment, research on drug resistance mechanisms has found that combination medication is one of the ways to overcome or reduce drug resistance.

Objective:To study the clinical manifestations, genetic profiles and treatment of Kagami-Ogata syndrome (KOS).Methods:A neonate admitted to our hospital was genetically diagnosed of KOS from amniocentesis sampling. The phenotype, genotype and treatment of the neonate were analyzed. Multiple databases were searched using key words including "Kagami-Ogata syndrome", "14q32 microdeletion syndrome", "coat-hanger ribs", "paternal uniparental disomy (pUPD)(14) " from the inception of the databases to Jan. 23th 2023. The clinical features, genotype and treatment of patients from the literature were summarized.Results:The neonate in our hospital was born at 30 weeks gestational age with a birth weight of 2 035 g. Prenatal ultrasound indicated overgrowth, bilateral fetal renal pelvis dilatation (FRPD), dilatation of intestines in lower abdomen, clenched hands with overlapping fingers and polyhydramnios. After birth, the neonate showed progressively worsening respiratory distress, distinct facial features (small jaw, short neck, flat nasal bridge, upward-facing nostrils, small and malformed ears with auricular deformity and narrow external auditory canals), bell-shaped thorax, diastasis recti and abnormal posture (overlapping fingers, clenched fists), as well as feeding difficulties, recurrent fever and dependence of respiratory support. Whole exome sequencing (WES) revealed a 268.2Kb deletion (101034306_101302541) in 14q32.2 region on both the neonate and the mother and the father was otherwise normal. The prognosis was poor and the parents refused further treatment. The neonate died at one month of age after two days of palliative care. A total of 36 articles were identified in the literature review, including 78 KOS cases with complete clinical data (a total of 79 cases adding our case).The primary clinical manifestations included distinctive facial and thoracic abnormalities (79/79, 100%), polyhydramnios (71/75, 94.7%), feeding difficulties (55/63, 87.3%), abdominal wall defects (57/72, 79.2%), joint contractures (39/70, 55.7%) and dependence of respiratory support (29/56, 51.8%). Long-term follow-up revealed 86.8% (59/68) experienced physical, movement and intellectual development delay, 39.7% (25/63) died or gave up treatments within five years. Genetic testing showed pUPD in 44 cases (55.7%), maternal deletions in 23 cases (29.1%), epimutations in 8 cases (10.1%) and unreported variations in 4 cases (5.1%).Conclusions:KOS is a genetic imprinting disorder affecting multiple organs. Prenatal screening can detect abnormalities such as polyhydramnios. Specific clinical signs, radiological findings and 14q32 gene analysis are helpful for the diagnosis of the disease.

This study aims to investigate the role and specific mechanisms of HO1 in mitigating lung inflammation after RSV infection.An RSV-infected mouse model was established,and lung tissues were collected for RNA-seq and differential gene expression analysis.HE staining and BALF cell counting were used to observe inflammation in the mouse lung tissues.Changes in HO1 expression were detected through immunohistochemistry,Western blotting,and qRT-PCR;inflammatory cytokine levels were assessed using qRT-PCR.HEMIN target proteins were predicted and analyzed by underwent GO and KEGG enrichment test;ROS levels in alveolar epithelial cells were measured using flow cytometry and immunofluorescence.Lysosomal changes were observed using transmission electron microscopy.The results demonstrated that HO1 expression was upregulated in the lung tissues of RSV-infected mice.Inducing HO1 expression alleviated lung tissue pathology,and lowered inflammatory cytokines IL-6 and TNF-α levels.RSV infection promoted ROS release and accumulation in lung epithelial cells,leading to an increase in autolysosomes.The induction of HO1 expression facilitated ROS clearance and reduced the number of autolysosomes.Therefore,the protective effect of HO 1 against oxidative stress reduces intracellular ROS generation,maintains organelle homeostasis,and reducing inflammatory cytokine IL-6,IL-8 and CXCL-10 levels.

Objective:To analyze the risk factors for premature infants with hemodynamically significant patent ductus arteriosus (hs-PDA) requiring surgical treatment, and to explore the indications for surgical treatment in premature infants with hs-PDA.Methods:A nested case-control study was conducted.The data of premature infants with gestational age<30 weeks who were diagnosed with hs-PDA in the Neonatal Intensive Care Unit of Peking Union Medical College Hospital from January 2007 to May 2020 were analyzed retrospectively.The hs-PDA patients treated surgically were included in the operation group.The hs-PDA patients of the same gestational age and gender who were not treated surgically were taken as the control group.The ratio of the case number between the operation and control groups was 1∶2.The clinical data during pregnancy, at birth and after birth of premature infants were compared between the 2 groups.The measurement data were tested by the independent sample t test or Mann- Whitney U test.The classification and enumeration data were compared by the Fisher′ s exact probability method.The risk factors for premature infants with hs-PDA requiring surgical treatment were analyzed by the conditional Logistic regression method. Results:A total of 182 premature infants with hs-PDA were enrolled in the study, including 10 in the operation group and 20 in the control group.The patients underwent PDA ligation 30.5(22.7, 37.0) d after birth, and the median preo-perative invasive ventilation duration was 9.7(17.5, 27.2) d. Compared with the control group(20 cases), the preterm infants in the operation group had a lower birth weight [(891.5±118.0) g vs.(1 054.4±230.2) g, t=2.091], a wider arterial duct diameter [3.2(2.8, 4.0) mm vs.2.0(2.0, 3.0) mm, Z=-3.300], and longer invasive ventilation duration [25.0(18.7, 38.2) d vs.3.0(1.0, 7.5) d, Z=-3.688]. Besides, the operation group applied the pulmonary surfactant for more times [2(1, 3) times vs.1(1, 2) times, Z=-2.440], and inhaled a higher concentration of oxygen on the 14 th day after birth [29(25, 36)% vs.21(21, 29)%, Z=-2.358] than the control group.Moreover, compared with the control group, the operation group took longer to achieve adequate enteral feeding [48.2(51.5, 63.5) d vs.42.5(23.5, 48.0) d, Z=2.789], and gained a higher maximum vasoactive inotropic score (VIS) [3.0(0, 3.5) points vs.0(0, 0) points, Z=-2.630]. The difference in all the above-mentioned indicators between the 2 groups was statistically significant (all P<0.05). Univariate Logistic regression analysis showed that the arterial duct diameter, application times of the pulmonary surfactant, the maximum VIS score, and the time taken to achieve sufficient enteral feeding were all related to the need for surgical treatment of hs-PDA in the operation group (all P<0.05). Multivariate Logistic regression analysis revealed that the invasive ventilation duration ( OR=0.747, 95% CI: 0.560-0.998, P=0.048) was an independent risk factor for hs-PDA premature infants requiring surgical treatment. Conclusions:The factors related to the need for surgical treatment in preterm infants with hs-PDA include a wide arterial duct diameter, multiple applications of the pulmonary surfactant, a high concentration of inhaled oxygen on the 14 th day, and the long time to achieve sufficient enteral feeding.The independent risk factor for the surgical treatment in hs-PDA children is the long invasive ventilation duration.

New threats posed by the emerging circulating variants of SARS-CoV-2 highlight the need to find conserved neutralizing epitopes for therapeutic antibodies and efficient vaccine design. Here, we identified a receptor-binding domain (RBD)-binding antibody, XG014, which potently neutralizes β-coronavirus lineage B (β-CoV-B), including SARS-CoV-2, its circulating variants, SARS-CoV and bat SARSr-CoV WIV1. Interestingly, antibody family members competing with XG014 binding show reduced levels of cross-reactivity and induce antibody-dependent SARS-CoV-2 spike (S) protein-mediated cell-cell fusion, suggesting a unique mode of recognition by XG014. Structural analyses reveal that XG014 recognizes a conserved epitope outside the ACE2 binding site and completely locks RBD in the non-functional "down" conformation, while its family member XG005 directly competes with ACE2 binding and position the RBD "up". Single administration of XG014 is effective in protection against and therapy of SARS-CoV-2 infection in vivo. Our findings suggest the potential to develop XG014 as pan-β-CoV-B therapeutics and the importance of the XG014 conserved antigenic epitope for designing broadly protective vaccines against β-CoV-B and newly emerging SARS-CoV-2 variants of concern.
Angiotensin-Converting Enzyme 2 ; Antibodies, Neutralizing ; Antibodies, Viral ; COVID-19 ; Epitopes ; Humans ; SARS-CoV-2/genetics* ; Spike Glycoprotein, Coronavirus/genetics*

Objective: To investigate the effect of oral nutritional supplements(ONS) on body weight loss and life quality in post-discharge patients with gastric and colorectal cancer. Methods: All the enrolled post-operative gastric or colorectal cancer patients were randomly divided into ONS group and control group. Body weight loss, middle arm circumference, triceps skinfold thickness and right-hand grip strength were measured and the Karnofsky score, ECOG score and QOL score were calculated 3 months after the discharge. Results: The body weight loss of gastric cancer patients was lower in ONS group than in control group since 2 months after discharge.(2 months after discharge: 1.65±2.11vs. 2.70±1.90 kg, t=-2.385 3, P=0.019 3; 3 months after discharge: 1.95±2.75vs. 3.67±2.29 kg, t=-3.134 7, P=0.002 4), There was no difference of body weight loss between two groups in colorectal cancer patients. The middle arm circumference, triceps skinfold thicknessand right-hand grip strength showed no statistic difference between two groups both in gastric and colorectal cancer patients. The Karnofsky score(56.82±13.65%vs. 51.71±9.72%, t=2.014 8, P=0.047 2) and QOL score(41.91±6.92 vs. 38.39±8.77, t=2.059 7, P=0.042 6) were higher in ONS group than in control group in gastric cancer patients. While all 3 types of scores had no difference between two groups in colorectal cancer patients. Conclusion ONS can efficiently reduce the body weight loss and improve the performance status and life qualityin post-discharge gastric cancer patients, but not in colorectal cancer patients.

Objective: To investigate the clinical characteristics, diagnostic approach, and treatment of infantile lactose intolerance, and to evaluate the diagnostic value of fecal pH. Methods: The feces and clinical data of all infants(less than 1 year old) diagnosed with simple diarrhea but without signs of infection were collected, who were treated at 4 Grade Ⅲ-Class-A hospitals within the period of June 2012 to June 2015 in Beijing were collected.Lactose intolerance was diagnosed based on urine galactose level, lactose tolerance test, and fecal pH.The clinical characteristics, therapeutic effects and detection methods of lactose tolerance group and intolerance group were analyzed.Then the diagnostic value of fecal pH was evaluated. Results: A total of 217 infants were enrolled in the study, consisting of 113 boys and 104 girls.Their age ranged from 3 to 330 days, 174 infants (80.2%) were less than 6 months old.Among them, 156 infants were diagnosed with lactose intolerance (71.9%), their median age 90.0 days (3-330 days), while the median age of the lactose tolerant group was 51.5 days (3-300 days). The incidence of lactose intolerance in infants less than 6 months old was 70.6%, and 76.7% in those older than 6 months.Clinical characteristics showed that more infants in the lactose intolerant group were breastfed compared with the lactose tolerant group [73/156 cases(46.8%) vs.16/61 cases(26.2%), χ²=7.666, P<0.05], the occurrence of loose foamy feces was higher in the lactose intolerant group [67/156 cases(42.9%) vs.15/61 cases (24.6%), χ²=6.287, P<0.05], the median duration of diarrhea in the lactose intolerant group was 30 days (1-210 days), and that in the lactose tolerant group was 30 days (1-300 days). The incidence of diarrhea more frequent than 10 times per day in the lactose intolerant group was 9.0% (14/156 cases), while that in the lactose tolerant group was 6.6% (4/61 cases). The rate of infection in the lactose intolerant group was similar to that in the lactose tolerant group [32/165 cases((20.5%) vs.17/61 cases(27.9%)]. The median time of recovery by feeding lactose-free formula milk was 2 days (1-60 days), recovery by feeding lactase lasted a median of 4 days (2-25 days), while recovery by using pro-biotics and dioctahedral smectite lasted a median of 2 days (1-5 days). The characteristics of fecal pH showed that mean pH value of fecal and the incidence of fecal pH<5.5 had no statistical significance between the lactose intolerant and tolerant group, between infants ≤6 months and infants>6 months, between the breastfeeding group and formula-feeding group, or between those with infection and those without infection (all P>0.05). Conclusions Infants with lactose intolerance often manifest foamy feces and tend to be breastfed.Lactose-free treatment efficacy was better than that with lactase.Clinical symptoms when combined with urine galactose level and lactose tolerance test can help diagnosis.However, the decrease of fecal pH proves to be unhelpful in aiding diagnosis.

.This study is to investigate the analgesic effect produced by intrathecal injection (ith) of oxysophoridine (OSR) and the mechanism of GABAA receptor. Warm water tail-flick test was used to detect the analgesic effect of OSR (12.5, 6.25, and 3.13 mg.kg-1 ith) and to observe the influence of GABA (gamma aminobutyric acid) agonist or antagonist on the analgesic effect of OSR in mice. Immunohistochemistry method were used to detect the influence of OSR (12.5 mg.kg-1, ith) on the GABAARalpha1 protein expression in spinal cord. The results obtained covers that OSR (12.5 and 6.25 mg.kg-, ith) alleviates pain significantly with the warm water tail-flick test (P<0.05, P<0.01), the rate of pain threshold increases by 68.45%; GABA and muscimol (MUS) produces analgesic synergism together with the OSR, picrotoxin (PTX) and bicuculline (BIC) antagonize the analgesic effect of OSR; OSR (12.5 mg.kg-1, ith) significantly increase the positive number of GABAARalpha1 nerve cell in spinal cord (P<0.01) and significantly decrease the average grey levels (P<0.01). In conclusion, OSR intrathecal injection has significant analgesic effect. And GABAA receptor in spinal cord is involved in the analgesic mechanism.

Objective To discuss the effect of QGY/CDDP hepatoma lines multi-drug resistance (MDR) reversed by gene transfection of mdr1,mrp-ASODN+ultrasound contrast agent+ultrasound.Methods The QGY/CDDP cells were transfected by mdr1,mrp ASODN+ultrasound contrast agent+ultrasound irradiation respectively and detected of the various indicators:cell adhesion rate,cell sensitivity to cell drug-resistance,the mRNA expression of mdr1 and mrp gene,the expression of P-gp and MRP protein. Results After mdr1-ASODN transfection,the drug sensitivity and expression of P-gp,MRP protein of QGY/CDDP cells were smaller changes(P＞0.05),and the rate of cells adherent and expression of resistance gene mRNA were obvious changes(P＜0.05).After mrp-ASODN transfection,the cells adherent rate,the drug sensitivity,the expression of resistance gene mRNA and P-gp,MRP protein were obvious changes respectively(P＜0.05),the experiment group(group 2')had bigger effects(P＜0.05).Conclusions mdr1. mrp-ASODN+ultrasound contrast agent+ultrasound irradiation could safely partly reverse MDR of hepatoma cells,which is a potential new approach for gene therapy.

Aim To investigate the role of mitochondrial aldehyde dehydrogenase 2 ( ALDH2) in the cardio-protection of ischemic postconditioning in isolated rat hearts. Methods Hearts isolated from male Sprague-Dawley rats were perfused on a langendorff apparatus and subjected to 30 min of regional ischemia( occlusion of left anterior descending artery) followed by 120 min reperfusion. Ischemic postconditioning was achieved by 6 cycles of 10 s reperfusion/10 s global ischemia starting at the beginning of reperfusion. The ventricular hemodynamic parameters and lactate dehydrogenase ( LDH) release during reperfusion were measured. The infarct size was measured by TTC staining method. The expressions of ALDH2,Bcl-2 and Bax at mRNA level of left anterior myocardium were detected by RT-PCR analysis. Results In contrast to ischemia and reperfusion,ischemic postconditioning improved the recovery of left ventricular developed pressure,rate pressure product during reperfusion,and reduced LDH release and infarct size. The expressions of ALDH2 mRNA level and the ratio of Bcl-2 /Bax were increased. Adminis-tration of ALDH2 antagonist cyanamide at the beginning of reperfusion attentuated the role of ischemic postconditioning. Conclusion Ischemic postconditioning plays a role in the cardioprotection partially through increasing mitochondrial ALDH2 mRNA expression.