[Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma].

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

[Analysis of the effects of low/intermediate dose of coagulation factor â § on 30 adult patients with severe hemophilia A in a single center].

Objective: To evaluate the clinical effects of low- and intermediate-dose factor Ⅷ (F Ⅷ) prophylaxis in Chinese adult patients with severe hemophilia A. Methods: Thirty adult patients with severe hemophilia A who received low- (n=20) /intermediate-dose (n=10) F Ⅷ prophylaxis at Nanjing Drum Tower Hospital affiliated with Nanjing University Medical College were included in the study. The annual bleeding rate (ABR), annual joint bleeding rate (AJBR), number of target joints, functional independence score of hemophilia (FISH), quality of life score, and health status score (SF-36) before and after preventive treatment were retrospectively analyzed and compared. Results: The median follow-up was 48 months. Compared with on-demand treatment, low- and intermediate-dose prophylaxis significantly reduced ABR, AJBR, and the number of target joints (P<0.05) ; the improvement in the intermediate-dose prophylaxis group was better than that in the low-dose prophylaxis group (P<0.05). Compared with on-demand treatment, the FISH score, quality of life score, and SF-36 score significantly improved in both groups (P<0.05), but there was no significant difference between the two groups (P>0.05) . Conclusion: In Chinese adults with severe hemophilia A, low- and intermediate-dose prophylaxis can significantly reduce bleeding frequency, delay the progression of joint lesions, and improve the quality of life of patients as compared with on-demand treatment. The improvement in clinical bleeding was better with intermediate-dose prophylaxis than low-dose prophylaxis.

Identification and Verification of the Ability of Cdk5 to Phosphorylate Deubiquitinating Enzyme BRCC3 In Vitro.

It is known that the expression of the deubiquitinating enzyme BRCA1-BRCA2-containing complex subunit 3 (BRCC3) and cyclin-dependent protein kinase 5 (Cdk5) is increased in Parkinson's disease (both are involved in neuroinflammatory response). However, the regulatory mechanism of Cdk5 on the post-translational modification of BRCC3 remains unclear. Here we studied whether Cdk5 phosphorylates BRCC3. Phosphorylation of BRCC3 by Cdk5 was predicted by GPS 5.0 software. His-BRCC3 plasmid was constructed by cloning the BRCC3 gene into pGEX-6P-1 vector, and then His-BRCC3 fusion protein was induced with isopropyl ß-d-1-thiogalactopyranoside and purified using His-Tag affinity chromatography purification agarose. Phosphorylation of BRCC3 fusion protein by Cdk5 in vitro was detected by mass spectrometry and Western blotting. The results showed that multiple phosphorylation sites were predicted by GPS 5.0, and the His-BRCC3 fusion protein was successfully induced and purified. In vitro kinase assay, Western blotting, and mass spectrometry showed that Cdk5 can phosphorylate BRCC3. It has been demonstrated that protein kinase Cdk5 can phosphorylate the deubiquitinating enzyme BRCC3 in vitro, which provides new data for further study on the mechanism of neurodegeneration.

[Emergency training need and effect evaluation analysis of novel coronavirus pneumonia in centers of disease control and prevention].

A questionnaire was used to investigate the emergency training needs of novel coronavirus pneumonia of disease prevention and control institutions in provinces, deputy provincial level regions and cities specifically designated in the state plan, and the effect evaluation of emergency training activities conducted by Chinese Center for Disease Control and Prevention (China CDC). The results showed that 67.4% of 47 disease prevention and control institutions (31/46) believed that the emergency training at the initial stage of the epidemic should be conducted as soon as possible, and the form of network training should be given priority. The training should focus on the urgently needed technologies such as epidemiological investigation, formulation and response of prevention and control strategies, laboratory testing, etc. The teaching materials should highlight pertinence and practicability and be presented in the form of electronic video. The average satisfaction score of the video training conducted by China CDC was (8.81±1.125) and the score of audio-video courseware was (8.97±0.893). The needs analysis and evaluation of novel coronavirus pneumonia prevention and control in disease prevention and control institutions could provide reference for the follow-up training and improve the emergency training management.

[Survey on provincial disease prevention and control professionals' attitudes and cognition to public health physician standardized training in China].

Objective: To understand the attitudes and cognition of disease control and prevention professionals at provincial level on public health physician standardized training and provide evidence for the improvement of the standardized training and exploration of more effective training mode in China. Methods: By cluster sampling, 2 193 professionals at provincial centers for disease control and prevention (CDC) in 6 provinces, including Jiangsu and Guangdong, Shanxi and Hubei,Sichuan and Xinjiang were selected as the study subjects, the sample size was estimated to be 1 933 persons. Results: A total of 1 716 provincial-level CDC professionals were surveyed, the support rate to the standardized training was 70.7%(1 213/1 716). The level of support was negatively associated with the educational level of professionals and their specialty of public health and preventive medicine. Of 875 public health and preventive medicine professionals, 61.6%(318/516) of those with master's degree or above supported the standard training for public health physicians, which was lower than 73.1%(225/308) of those with bachelor's degree and 86.3%(44/51) of those with college degree or below. There were 14.9%(232/1 555) of the respondents suggested a two year training, and 60.4%(933/1 544) suggesting a field training mode. In terms of training content, 86.6%(1 355/1 564) suggesting "epidemiological survey and public health practice", and 76.7%(1 199/1 564) suggesting "basic theories and methodology". Conclusions: In general, the professionals of provincial CDC showed a relatively low interest in the standardized training for public health physicians and failed to reach a consensus. Besides, they were ill-informed about current training duration, method and content. Thas, the professionals at provincial CDC are suggested to be the key target-population whom should be mobilized during the training pilot period, especially the highly educated ones with relevant specialties of public health. It is suggested that public health physician standardized training should to be implemented in whole CDC system to reach full consensus based on its practical achievements and effects. It is also suggested to establish public health graduate medical education system in China.

[Current situation and suggestions of public health personnel training in disease control and prevention institutions].

Under the background that the national health has become the national priority development strategy, it is essential to speed up public health ability among talents. Based on the consulting project of the Chinese Academy of Engineering, "Research on the training strategy of medical and health personnel in China", this paper analyzes the current situation and existing problems of public health personnel training in disease control and prevention institutions. Based on three stages of public health education, this paper puts forward that the public health personnel training should first solve the problem of public health personnel team construction and create programs on college education-post graduate education-continuing education. Through the personnel training system, different training modes are designed for other groups of people to improve the ability of public health personnel in an all-around way.

[Prognostic factor analysis of patients with unresectablelung squamous cell carcinoma].

Objective: To investigate the prognostic factors associated with unresectable (stage Ⅲa-Ⅳ, according to the 7th edition of the AJCC cancer staging manual) lung squamous cell carcinoma. Methods: We retrospectively analyzed 350 patients with inoperable locally advanced, recurrent or metastatic lung squamous cell carcinoma who were admitted to the First Affiliated Hospital of Chinese Medical University from January 2005 to June 2018. The clinical pathological data, treatment and survival follow-up information of the patients were collected. Kaplan-Meier survival was used to compare the overall survival rate of different risk groups. Univariate analysis and multivariate Cox regression analysis were used to determine the independent prognostic factors. Results: A total of 350 patients were enrolled. The median overall survival (OS) of these patients was 16.7 months. Univariate analysis showed the stage, Eastern Cooperative Oncology Group(ECOG), first-line chemotherapy evaluation (RECIST version 1.1), radiation therapy, number of systemic chemotherapy lines, carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), C reactive protein (CRP), lactate dehydrogenase (LDH), whether liver, brain, boneor metastasis were associated with the OS of patients with advanced lung squamous cell carcinoma (all P<0.05). Multivariate analysis showed that ECOG score (HR=1.855, 95% CI: 1.063-3.239, P=0.030), whether underwent lung resection (HR=0.476, 95%CI: 0.302-0.751, P=0.001), first-line chemotherapy evaluation [stable disease (SD): HR=0.293, 95%CI: 0.159-0.540, P<0.001; complete response (CR)+ partial response (PR): HR=0.223, 95%CI: 0.120-0.413, P<0.001], CRP (HR=1.715, 95% CI: 1.080-2.723, P=0.042), LDH (HR=1.116, 95%CI: 0.780-1.596, P=0.002) and CEA (HR=1.855, 95%CI: 1.361-2.528, P<0.001) before chemotherapy, liver metastasis (HR=2.453, 95%CI: 1.461-4.120, P=0.001) are independent prognostic factors for patients with unresectable lung squamous cell carcinoma. Conclusion: The ECOG score, surgical treatment history, first-line chemotherapy, LDH, CEA and CRP before chemotherapy, liver metastasis are independent prognostic factors for patients with advanced lung squamous cell carcinoma.

[A survey of attitudes to and demands on internship in graduates majoring in preventive medicine in 6 colleges and universities in China].

Objective: To understand the internship of students majoring in preventive medicine in 6 colleges and universities in China, and provide reference suggestions for the improvement of internship arrangement. Methods: By using the method of combined clustering and convenient sampling, the fifth grades students majoring in preventive medicine in six universities in the eastern, central and western China were surveyed by using questionnaires to collect the information of their attitudes (to) and suggestions for clinical and public health internships. Results: A total of 596 students were surveyed. In terms of the benefits of clinical internship and public health internship, students who thought that the internship was fruitful accounted for >88%, and more students thought that reform is needed in clinical internship compared with public health internship. In clinical internship, the students through that the time arrangement was not appropriate enough (95, 39.58%), the content should be more detailed and in-depth (73, 30.42%) and the content did not conform to the professional direction (54, 22.50%). In public health internship, the students thought that the time arrangement was not appropriate (77, 45.56%), the content should be more detailed and standardized (65, 38.46%) and the types of internship bases should be more diversified (20, 11.83%). Conclusions: The undergraduates majoring in preventive medicine felt to be benefited from clinical practice and public health internships and thought they are of necessity. At the same time, there are still many problems which needs to be improved in the two types of internships. It is necessary to make joint efforts from students, teachers, colleges and practice bases to promote the continuous improvement of undergraduate internship.

Germline mutations of DICER1 in Chinese women with BRCA1/BRCA2-negative familial breast cancer.

Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA-producing machinery; germline mutations of DICER1 have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumors, and other cancers. Low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remain unknown. Sixty-five breast cancer probands from BRCA1/BRCA2-negative Chinese breast cancer families were screened for germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as controls. A polymerase chain reaction sequencing assay was used to screen for mutations in coding regions and at the exon-intron boundaries of DICER1. All variants in introns were evaluated using the NNSplice software to determine the potential splicing effect. A total of 12 germline variants were found, including 11 variants in introns and 1 variant in the 3'-non-coding region. Four variants (IVS8-205 C>T, IVS11+131 delGAAA, IVS16+42 delTA, and IVS19+160 T>C) were novel. Three variants (IVS11+105 C>T, IVS16+42 delTA, and 6095 T>A) may affect splice sites. None of the observed variants appeared to be disease-related, suggesting that germline mutations in DICER1 are rare or absent in familial breast cancer patients.

Mutation and abnormal expression of the fragile histidine triad gene in nasopharyngeal carcinoma.

OBJECTIVE: To determine alterations of fragile histidine triad (FHIT) gene in nasopharyngeal carcinoma and the correlation of FHIT gene with nasopharyngeal carcinogenesis. STUDY DESIGN: Prospective study. METHODS: A total of 28 nasopharyngeal carcinoma and 16 normal nasopharyngeal epithelium specimens were examined for abnormalities of FHIT gene by nested reverse-transcriptase-polymerase chain reaction and DNA sequencing. RESULTS: The deletion of FHIT gene was not observed in 16 normal nasopharyngeal epithelium specimens. In 28 cases of nasopharyngeal carcinoma tissues, 12 (42.9%) exhibited FHIT aberrant transcripts. Complementary DNA sequencing revealed exonic deletion, small DNA insertion, synonymous mutation in exon 8, or frameshift mutation in exon 5. CONCLUSIONS: The present results suggest that the FHIT gene may play an important role in the pathogenesis of nasopharyngeal carcinoma and may be one of the candidate tumor suppressor genes in nasopharyngeal carcinoma.

Distinct domains of IFNalpha mediate immune and analgesic effects respectively.

Interferon-alpha (IFNalpha) is not only an immunoregulatory factor, but is also an analgesic molecule. The analgesic effect of IFNalpha was mediated by mu opioid receptor. After the 129th Tyr residue of human IFNalpha was mutated to Ser, the antiviral activity almost disappeared, but there still remained a strong analgesic activity that could be blocked by naloxone. These results indicate that there exist distinct domains in the IFNalpha molecule, which mediate immune and analgesic effects respectively, and suggest that there are different receptor mechanisms inducing immune and analgesic effects of IFNalpha. However, although the antiviral activity of IFNalpha decreased to 34.1% of wild type IFNalpha after the 122nd Tyr residue was changed to Ser, the analgesic activity of this mutant was lost completely. There were significant cross reactivities between INFalpha and anti-opioid sera. These studies show strong structural and functional similarities between INFalpha and opioid peptides, and inferred that the analgesic domain locates around the 122nd Tyr residue of IFNalpha molecule in tertiary structure.

[Distinct structural bases of the immunoregulatory and central analgesic effects of IFNalpha].

Interferon-alpha (IFNalpha), a cytokine, is also an analgesic molecule. There is significant cross reactivity between IFNalpha and anti-opioid sera, suggesting a strong antigenic relatedness between human IFNalpha molecules and opioid peptides. Different structural basis of the immunoactivity and analgesic effect of IFNalpha can be demonstrated by different reactivities of the two reactions towards different mutants of IFNalpha obtained by using the site-directed mutagenesis. When the 129th Tyr residue of human IFNalpha was mutated to Ser, the immunoactivity of the mutant almost disappeared, while the strong analgesic activity still persisted, which could be blocked by naloxone. These results indicate that there exist distinct domains in the IFNalpha molecule, which mediate immune and analgesic effects differentially, and that the receptor mechanism underlying immune and analgesic effects of IFNalpha may be different.