[Impact of autologous hematopoietic stem cell transplantation on the efficacy of CAR-T treatment of relapsed/refractory multiple myeloma].

Objective: To evaluate the effect of autologous hematopoietic stem cell transplantation (ASCT) on the treatment of relapsed/refractory multiple myeloma (RRMM) with chimeric antigen receptor T cell (CAR-T) therapy. Methods: A retrospective cohort study. The clinical data of 168 patients with RRMM who underwent CAR-T therapy at the Department of Hematology, Xuzhou Medical University Hospital from 3 January 2020 to 13 September 2022 were analyzed. Patients were classified into a transplantation group (TG; n=47) and non-transplantation group (NTG; n=121) based on whether or not they had undergone ASCT previously. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the levels of CD3, CD4, CD8, CD19, CD56 and natural killer (NK) cells before CAR-T infusion were analyzed by χ2 test, Kaplan-Meier method and independent sample t-test. Results: Among 168 patients with RRMM, 98 (58.3%) were male. The median age of onset was 57 (range 30-70) years. After CAR-T therapy, the ORR of patients was 89.3% (92/103) in the NTG and 72.9% (27/73) in the TG. The ORR of the NTG was better than that of the TG (χ2=5.71, P=0.017). After 1 year of CAR-T therapy, the ORR of the NTG was 78.1% (75/96), and that of the TG was 59.4% (19/32). The ORR of the NTG was better than that of the TG (χ2=4.32, P=0.038). The median OS and PFS in the NTG were significantly longer than those in the TG (OS, 30 vs. 20 months; PFS, 26 vs. 12 months; both P<0.05). The CD4 level before CAR-T infusion in the TG was significantly lower than that in the NTG (25.65±13.56 vs. 32.64±17.21; t=-2.15, P=0.034), and there were no significant differences in the counts of CD3, CD8, CD19, CD56, and NK cells between the TG and NTG (all P>0.05). Conclusion: Among patients suffering from RRMM who received CAR-T therapy, patients who did not receive ASCT had significantly better outcomes than those who had received ASCT previously, which may have been related to the CD4 level before receiving CAR-T therapy.

[Impact of different diagnostic criteria for assessing mild micro-hepatic encephalopathy in liver cirrhosis: an analysis based on a prospective, multicenter, real-world study].

Objective: To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test. Methods: This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ (2) test. A kappa test was used to compare the consistency between groups. Results: After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea (Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences (P < 0.001). Conclusion: The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

[Correlation between mutation of p53 gene 2-4 exons from peripheral blood and HPV16 positive cervical cancer susceptibility and clinical significance].

Objective: To detect mutations of p53 gene 2-4 exons from peripheral blood and to explore their relevance in HPV16-positive cervical cancer susceptibility and clinical significance. Methods: Collected firstly cases from the Third Affiliated Hospital of Kunming Medical University from October 2012 to April 2014, included 167 cases HPV16-postive cervical cancer and 160 cases HPV-negative healthy women. Genomic DNA from the host peripheral venous blood was taken, mutations of p53 gene 2-4 exons were analyzed with software DNAstar after PCR and bidirectional sequencing. Meanwhile, mutations of p53 gene 2-4 exons among different clinicopathological characteristics in HPV16-postive cervical cancer were distinguished. Results: (1) Three mutations and an 16-bp insertion/deletion sequences were found in p53 gene exons 2-4, included C/G mutation of single nucleotide polymorphism (SNP) 11827 in intron2, A/C mutation of SNP11992 in intron3, C/G mutation in codon 72 (rs1042522) of exon4 and 16-bp (acctggagggctgggg) repeat insertion or deletion in intron3 (rs17878362), while deletion recorded as A1, insertion recorded as A2. No significant differences were found in each point allele and genotype frequency (P>0.05) . (2) Stratified analysis for cervical cancer group resulted with some differences. Compared group of non-squamous carcinoma with squamous carcinoma group, there were obviously decreased in allete A2 [11.8% (4/34) vs 3.5% (10/284) ; χ(2)=4.90, P=0.027], genotype A1A2 [4/17 vs 7.0% (10/142) ; χ(2)=5.14, P=0.023], and haplotype C-A2 [11.8% (4/34) vs 3.5% (10/284) ; χ(2)=4.91, P=0.027]. Compared with poorly differentiated group, allele C of SNP11827 and rs1042522 were obviously decreased in medium high differentiation group [50.8% (61/120) vs 38.8% (62/160) ; χ(2)=4.07, P=0.044], while haplotype G-A1 were apparently higher [49.2% (59/120) vs 61.2% (98/160) ; χ(2)=4.07, P=0.044], genotype GG of SNP11827 and rs1042522 were obviously decreased in superficial myometrial invasion depth group than that in deep myometrial invasion depth group [46.3% (25/54) vs 21.1% (8/38) ; χ(2)=7.06, P=0.029]. No significant differences were found between stage Ⅰ and Ⅱ, pelvic lymph node metastasis or not (all P>0.05) . Conclusions: No obvious correlation is found between polymorphisms in exons 2-4 of p53 gene and susceptibility of HPV16-postive cervical cancer. But the patient with allete C and A2, genotype GG and A1A2, haplotype C-A2 and G-A1 may be increase risk of poorly differentiation, deep muscular invasion and bad pathological type. Analysis of p53 gene polymorphism may be provide a basis for the prognosis evaluation and individualized treatment of cervical cancer.

[Observation of liver indexes in patients with relapsed/refractory multiple myeloma treated with CAR-T-cells based on BCMA].

Objective: To observe the characteristics of the evolution of liver indexes in patients with relapsed/refractory multiple myeloma (RRMM) treated with CAR-T-cells based on BCMA. Methods: Retrospective analysis was performed of patients with RRMM who received an infusion of anti-BCMA CAR-T-cells and anti-BCMA combined with anti-CD19 CAR-T-cells at our center between June 1, 2019, and February 28, 2023. Clinical data were collected to observe the characteristics of changes in liver indexes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL) in patients, and its relationship with cytokine-release syndrome (CRS) . Results: Ninety-two patients were included in the analysis, including 41 patients (44.6%) in the group receiving a single infusion of anti-BCMA CAR-T-cells, and 51 patients (55.4%) in the group receiving an infusion of anti-BCMA combined with anti-CD19 CAR-T-cells. After infusing CAR-T-cells, 31 patients (33.7%) experienced changes in liver indexes at or above grade 2, which included 20 patients (21.7%) with changes in one index, five patients (5.4%) with changes in two indexes, and six patients (6.5%) with changes in three or more indexes. The median time of peak values of ALT and AST were d17 and d14, respectively, and the median duration of exceeding grade 2 was 5.0 and 3.5 days, respectively. The median time of peak values of TBIL and DBIL was on d19 and d21, respectively, and the median duration of exceeding grade 2 was 4.0 days, respectively. The median time of onset of CRS was d8, and the peak time of fever was d9. The ALT, AST, and TBIL of patients with CRS were higher than those of patients without CRS (P=0.011, 0.002, and 0.015, respectively). CRS is an independent factor that affects ALT and TBIL levels (OR=19.668, 95% CI 18.959-20.173, P=0.001). The evolution of liver indexes can be reversed through anti-CRS and liver-protection treatments, and no patient died of liver injury. Conclusions: In BCMA-based CAR-T-cell therapy for RRMM, CRS is an important factor causing the evolution of liver indexes. The evolution of liver indexes after CAR-T-cell infusion is transient and reversible after treatment.

[A multi-center retrospective study of perioperative chemotherapy for gastric cancer based on real-world data].

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.

Identification and molecular characterization of a new potyvirus from Panax notoginseng.

A potyvirus causing distortion and mosaic symptoms in the herbal plant Sanqi (Panax notoginseng) was isolated from Yunnan province, China, and the complete nucleotide sequence of one isolate and the partial sequences of two other isolates were determined. The viral RNA genome comprised 9,750 nt excluding the 3'-terminal poly(A) tail, with the capacity to encode a single polyprotein of 3,089 amino acids. Phylogenetic analysis with other completely sequenced potyviruses revealed that the virus in this study was most closely related to plum pox virus, with 56.3% nt identity in the genomic RNA sequence and 53.3% aa identity in the polyprotein. However, the most closely related 3'-terminal sequences were from four partially sequenced potyviruses infecting plants of the family Apiaceae (67.7-75.3% nt identity and 73.8-76.7% aa identity in their coat protein cistrons), especially Angelica virus Y. These results suggest that this virus isolate should be designated a member of a new species in the genus Potyvirus, which is tentatively named Panax virus Y (PanVY).

[Synthesis and antifertility actions of gossypol derivatives and phenol aldehydes].

A series of trihydroxynaphthaldehydes, polyhydroxybiphenol-asdehydes, polyhydroxybinaphthyl aldehydes and some gossypol derivatives were synthesized for antifertility experimental studies.

[Inhibitory effects of neferine and tetrandrine on portal vein and papillary muscle in rats].

To determine the vascular selectivity, the inhibitory effects of verapamil (Ver), neferine (Nef), and tetrandrine (Tet) on the spontaneous contractile force of portal vein and contractile force of the paced papillary muscle of left ventricle were studied in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The vascular selectivity was expressed by the IC50 ratio (IC50 for papillary muscle/IC50 for portal vein). The results showed that the vascular selectivity values of Ver, Nef, and Tet were 1.15, 0.32, and 0.20, respectively in WKY and 0.80, 0.24, and 0.10, respectively in SHR. It is concluded that Nef and Tet, in contrast with Ver which is devoid of selectivity for either tissue, are more liable to inhibit the myocardium than the vascular smooth muscle. In addition, the IC50 value of Tet for inhibition of the portal vein in SHR was nearly 10-fold higher than that in WKY (237 and 27 mumol.L-1, respectively). This indicates that the response of portal vein to Tet is decreased in SHR.

Chlorpromazine inhibits hepatocyte apoptosis caused by withdrawal of phenobarbital in mice.

AIM: To study the inhibitory effect of chlorpromazine (Chl), verapamil, and aspirin on hepatocyte apoptosis induced by the cessation of phenobarbital (Phe) treatment in mice. METHODS: Liver DNA content, ratio of liver weight/body weight, DNA fragmentation, DNA electrophoresis, the end-labeling test (TUNEL), and the morphologic changes of liver cells as indices of liver mass and hepatocyte apoptosis were applied to investigate (1) the kinetic process of hepatocyte proliferation induced by Phe 75 mg.kg-1 i.p. and the regression of hyperplastic liver caused by withdrawal of Phe in mice, (2) the effect of Chl 25 mg.kg-1, verapamil 50 mg.kg-1 or aspirin 60 mg.kg-1 i.p. on mouse hepatocyte apoptosis, and (3) the time course of effects of Chl on the regression of liver size and DNA fragmentation content after withdrawal of Phe. RESULTS: The process of hepatocyte proliferation and regression induced by administration and withdrawal of Phe in mice consisted of 4 phases: proliferation, plateau, rapid regression, and slow regression phases. In the rapid regression phase, the typic changes of hepatocyte apoptosis were found, which was prevented in early period by the Ca(2+)-calmodulin antagonist Chl, but not by verapamil or aspirin. CONCLUSION: The Ca(2+)-calmodulin played an important role in the hepatocyte apoptosis caused by withdrawal of Phe.