Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.
Humans ; Middle Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Chemoradiotherapy ; Immune Checkpoint Inhibitors/therapeutic use* ; Neoadjuvant Therapy ; Prospective Studies ; Rectal Neoplasms/pathology* ; Thrombocytopenia/drug therapy* ; Treatment Outcome ; Adult ; Aged

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.
Bronchopulmonary Dysplasia/epidemiology* ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; Pregnancy ; Respiratory Distress Syndrome, Newborn/epidemiology* ; Retrospective Studies ; Treatment Outcome

Objective:To investigate the protective effect of intermittent fasting on radiation-induced cognitive impairment and the possible underlying mechanism.Methods:A total of 36 male 7-week old c57BL/6J mice were divided into Sham-irradiation and ad libitum (Sham-AL) group, irradiation and ad libitum (IR-AL) group, and irradiation add intermittent fasting (IR-IF) group according to the random number table method, with 12 mice in each group. The cognitive function of mice was assessed by novel object recognition task. The expressions of autophagy gene 5 (ATG5), microtubulesas sociated protein light chain II (LC3II), voltage dependent anion channel protein 1 (VDAC1), interleukin-1β (IL-1β), synaptophysin (SYP), synapsin I (SYN-1), and postsynaptic density 95 (PSD95) were tested by Western blot. The location of VDAC1 in mice hippocampus was detected by immunofluorescence.Results:The discrimination index (-22.45 ± 16.76) of IR-AL group was significantly ( t=3.032, P<0.05) lower than that of Sham-AL group (30.02 ± 9.05). Compared to Sham-AL group, IR-AL group had a decreased expressions of autophagy-related proteins (ATG5 and LC3II), mitochondrial marker (VDAC1), inflammatory factors (IL-1β) as well as synapse-associated proteins SYP, SYN-1 and PSD95 ( t=2.49, 2.19, 2.40, 3.47, 2.87, 2.25, 2.17, 2.31, P<0.05). Compared to IR-AL group, IR-IF group had an increased discrimination index (21.22 ± 5.62) and the increased expressions of ATG5, LC3II, VDAC1, IL-1β, SYP, SYN-1, and PSD95 ( t=2.70, 2.88, 2.71, 3.18, 3.18, 3.11, 3.30, 3.35, 2.53, P<0.05). The immunofluorescence assay revealed that VDAC1 was co-expressed with the markers of astrocytes (GFAP) and microglia (IBA-1), but not with neurons (NEUN). Conclusions:Intermittent fasting could greatly improve the cognitive function of irradiated mice possibly by upregulating VDAC1 expression, induce autophagy, and inhibit the release of inflammatory factors and protecting the synapticplasticity in the hippocampus.

With prominent medicinal value, Gelsemium elegans has been overexploited, resulting in the reduction of the wild resource. As a result, artificial cultivation turns out to be a solution. However, this medicinal species is intolerant to low temperature, and thus genes responding to the low temperature are important for the cultivation of this species. Based on the transcriptome database of G. elegans at 4 ℃, 29 differentially expressed GeERF genes were identified. Bioinformatics analysis of 21 GeERF gene sequences with intact open reading frames showed that 12 and 9 of the GeERF proteins respectively clustered in DREB subgroup and ERF subgroup. GeDREB1 A-1-GeERF6 B-1, with molecular weight of 23.78-50.96 kDa and length of 212-459 aa, were all predicted to be hydrophilic and in nucleus. Furthermore, the full-length cDNA sequence of GeERF2B-1 was cloned from the leaves of G. elegans. Subcellular localization suggested that GeERF2B-1 was located in the nucleus. According to the quantitative reverse-transcription PCR(qRT-PCR), GeERF2B-1 showed constitutive expression in roots, stems, and leaves of G. elegans, and the expression was the highest in roots. In terms of the response to 4 ℃ treatment, the expression of GeERF2B-1 was significantly higher than that in the control and peaked at 12 h, suggesting a positive response to low temperature. This study lays a scientific basis for the functional study of GeERF transcription factors and provides gene resources for the improvement of stress resistance of G. elegans.
DNA, Complementary ; Gene Expression Regulation, Plant ; Phylogeny ; Plant Proteins/metabolism* ; Temperature ; Transcription Factors/metabolism*

To establish the UPLC fingerprint of Zhongyi Angong Niuhuang Pills, in order to evaluate its quality by chemical pattern recognition. The method was developed on a column of Poroshell 120 EC-C_(18), with methanol-0.1% formic acid solution as the mobile phase for gradient elution at a flow rate of 0.4 mL·min~(-1). The column temperature was 30 ℃,and the detective wavelength was 254 nm. The similarity of 24 batches of Angong Niuhuang Pills was compared by using Traditional Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System(2004 A). Hydrophobic cluster analysis,principal components analysis and partial least squares discriminant analysis were conducted by using SIMCA 13.0 software to investigate different components among these products. The UPLC characteristic fingerprint was established in this study. And 17 common peaks were identified by standard reference and UPLC-MS. The similarity of 24 batches samples were above 0.980,which can be classified into three categories for pattern recognition. Baicalin,berberine,jatrorrhizine,wogonin and wogonoside were identified as the main markers that cause differences of various batches. The method is simple,rapid,accurate and reproducible,and can provide scientific basis for improving the quality standard of Zhongyi Angong Niuhuang Pills.
Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal/chemistry* ; Tandem Mass Spectrometry

Purpose To investigate the expression of CYP4 A11 and CYP4 A22 in triple-negative breast carcinoma (TNBC) and its relationship with clinicopathological features and M2 tumor-associated macrophages (TAMs). Methods 72 cases of TNBC with clinical and pathological data were collected. The expression of CYP4 A11 and CYP4 A22 in the carcinoma cells and the expression of CD68 and CD163 of the TAMs were detected by immunohistochemically and analyzed with image processing software. The relationship between the expressions of CYP4 A11 and CYP4 A22 with clinicopathologic features and its correlation of the M2 state of TAMs was studied. Results Both the immunohistochemically staining scores of CYP4 A11 and CYP4 A22 were higher in cancer tissues than that in breast tissues (P<0.001, P<0.001). The higher expression of CYP4 A11 was associated with tumor diameter increase (P<0.001), lymph node metastasis (P<0.001), higher clinical stage (P<0.001) and higher Ki-67 index (P=0.011). Both the positive rates of CD68 and CD163 in the high expression group of CYP4 A11 were higher than those in the low expression group of CYP4 A11 (P=0.021, P<0.001). The higher expression of CYP4 A22 was associated with lymph node metastasis (P<0.001), higher clinical stage (P=0.006), higher recurrence rate (P<0.001), and higher Ki-67 index (P=0.040).The positive rates of CD163 in the high expression group of CYP4 A22 was higher than that in the low expression group of CYP4 A22 (P<0.001). Conclusion Both the expression of CYP4 A11 and CYP4 A22 may be associated with M2 polarization state of TAMs, high proliferative activity and lymph node metastasis in the TNBC.

Objective To investigate the clinical efficacy and safety of domestic imatinib in the treatment of gastrointestinal stromal tumor (GIST). Methods Clinicopathological and follow-up data of GIST patients who received domestic imatinib treatment from January 2014 to December 2017 in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were analyzed retrospectively. The treatment efficacy and adverse reactions were analyzed. Results A total of 35 patients included 20 males and 15 females with a median age of 53 years old (28-79 years old). Among all the patients, 25 with primary GIST underwent complete resection, in which 20 cases were classified as high risk and 5 as moderate risk according to the risk stratification. Of the remaining 10 recurrent/metastatic or unresectable GIST patients, 6 cases had metastasis in liver, 2 cases had metastasis in peritoneum, 1 case had extensive abdominal and pelvic metastasis, and the other 1 case was initially unresectable. The follow-up data of all the 35 patients were available, with a median follow-up time of 25 months (4-49 months). Twenty-five primary patients with complete resection received adjuvant therapy with a median time of 14 months (4-44 months). The median time of follow-up was 25 months (4-49 months), and none of the primary patients was detected with recurrence or metastasis of GIST. Meanwhile, of the 10 patients with recurrent/metastatic or unresectableGIST, the median time of medicine-taking was 24 months (3-49 months). Seven of 10 patients received imatinib monotherapy, including 5 cases of partial remission and 2 cases of stable disease. The other 3 patients with localized progression received complete resection along with imatinib therapy. All the 10 patients achieved durable clinical benefit. Twenty-seven patients (77.1％) experienced adverse events, and only 1 case (2.9 ％) had grade 3 adverse events. Conclusion Domestic imatinib is effective and safe for patients who received adjuvant therapy after complete resection of primary GIST as well as those with recurrent/metastatic or unresectable GIST, but it remains to be further confirmed by large samples of prospective studies.

Coronary artery disease (CAD)is a major cause of death and disability worldwide, and consumes a considerable amount of medical resources every year.Clopidogrel is a first-line antiplate-let therapy for CHD, butit is associated with substantial variability in PK and pharmacodynamics re-sponse. To date, gene variants explain only a smallproportion of the variability.The study aimed to identify new genetic loci-modifying antiplatelet response to clopidogrel in Chinese patients with CAD by a systematic analysis combining antiplatelet effects and PK, and further to investigate the PON1 gene promoter DNA methylation and genetic variations possibly influencing clinical outcomes in pa-tients undergoing PCI. We identified novel variants in two transporter genes (SLC14A2rs12456693, ATP-binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reac-tion unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically im-proved the predictability of PRU variability to 37.7％. The associations between these loci and PK pa-rameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P<0.05). Rs2254638 was further identified to exert a marginal risk effect formajor adverse cardiac events in an independent cohort.Multivariate logistic regression analysis indicated that PON1methylation level at CpG site-161 (OR=0.95; 95％ CI=0.92–0.98;P<0.01)and the use of angiotensin converting enzyme inhibitors(OR=0.48;95％ CI=0.26–0.89;P<0.01) were associated with decreased risk of bleeding events. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment.The ab-normal expression of DNA methylation-regulating key genes in the pharmacokinetic and pharmacody-namics pathways of clopidogrel and aspirin may modify clinical outcomes in dual antiplatelet-treated pa-tients undergoing PCI.

Purpose To investigate the expression of sphingosine-1 phosphate receptor 1 (S1PR1) and sphingosine-1 phosphate receptor 4 (SIPR4) in triple negative breast carcinoma (TNBC) and to evaluate its correlation with the clinicopathologic features of TNBC. Methods 72 cases of tissue slides of TNBC were stained immunohistochemically and analyzed with image processing to calculate the S1PR1 and S1PR4 expression. Correlations of the S1PR1 and S1PR4 expression with the clinicopathologic features of TNBC were studied. Results Ki-67 index of high, moderate and low expression of the S1PR1 in TNBC were 48.89％, 36.11％ and 26.48％, respectively. The difference among them was significance (P＜0.001). Ki-67 index of high, moderate and low expression of the S1PR4 in TNBC were42.83％, 31.43％ and 28.93％, respectively. The difference among them was significance (P = 0.007 ). The positive rate of lymph node of high, moderate and low expression of the SI PR1 in TNBC were 31.4％, 48.6％ and 20.0％, respectively. The difference among them was significance (P = 0.012). The positive rate of lymph node of high, moderate and low expression of the S1PR4 in TNBC were 54.3％, 40.0％ and 5.7％, respectively. The difference among them was significance (P=0.010). The CD68 positive rate of high, moderate and low expression of the S1PR1 in TNBC were 47.22％, 42.59％ and31.48％, respectively. The difference among them was significance (P = 0.036). Both the difference of survive rate among high, moderate and low expression of the S1PR1 and S1PR4 were not significance (P = 0.209 and P =0.593 ). Conclusion High expression of S1PR1 and S1PR4 may contribute to the cellular proliferation and lymph node metastases in TNBC. The survive rate of TNBC maybe not related with both the S1PR1 and S1PR4 expression.

Objective: To provide the experimental basis for the coherence of the indirect bond position by comparing the position of the bracket on the digital occlusal model and the position of the transfer to the initial plaster model. Methods: Fifteen digitized models were selected for the brackets on the dental denture model, the brackets were transferred to the initial plaster model by indirect bond transfer trays, The line distance between each bracket position in digital dental model and initial plaster model was measured with OrthoRx software. Results : The difference between the position of the orthodontic brackets and the position of the initial plaster model was less than 0.20 mm, and the difference was statistically significant (P < 0.05). Conclusion The position of the bracket on the digital occlusal model is consistent with that of the original plaster model, which provides a theoretical basis for digital indirect bonding.