Early failure is still a poor prognostic factor in patients with relapsed or refractory large B-cell lymphoma in the era of CAR T-cell therapy.

Patients with refractory or relapsed (R/R) large B-cell lymphoma (LBCL) refractory to first-line chemotherapy or with early relapse have poor outcomes. While chimeric antigen receptor (CAR) T-cell therapy has impressive efficacy after two or more lines of chemotherapy, it's still uncertain if these outcomes remain consistent in the context of third-line CAR T-cell therapy. We conducted a retrospective study of 107 R/R LBCL patients. Patients with relapse 12 months or more after their first-line chemoimmunotherapy (late failure: n = 25) had significantly longer overall survival (OS) than patients with refractory disease or relapse within 12 months (early failure: n = 82) (median OS: not achieved vs. 18.4 months; P < 0.001). Among patients who proceeded to autologous hematopoietic stem-cell transplantation (auto-HSCT), those with late failure had significantly longer event-free survival (EFS) than those with early failure (median EFS: 26.9 vs. 3.1 months; P = 0.012). However, no significant difference in EFS was detected among patients who underwent CAR T-cell therapy (median EFS: not reached vs. 11.8; P = 0.091). Cox regression with restricted cubic spline demonstrated that timing of relapse had significant impact on EFS in patients with auto-HSCT but not in patients with CAR T-cell therapy. Of patients who were scheduled for CAR T-cell therapy, those with late failure were significantly more likely to receive CAR T-cell therapy than those with early failure (90% vs. 57%; P = 0.008). In conclusion, patients with early failure still experienced poor outcomes after the approval of third-line CAR T-cell therapy.

N-terminal region of RecQ4 inhibits non-homologous end joining and chromatin association of the Ku heterodimer in Xenopus egg extracts.

RecQ4, a member of the RecQ helicase family, is required for the maintenance of genome integrity. RecQ4 has been shown to promote the following two DNA double-strand break (DSB) repair pathways: non-homologous end joining (NHEJ) and homologous recombination (HR). However, its molecular function has not been fully elucidated. In the present study, we aimed to investigate the role of RecQ4 in NHEJ using Xenopus egg extracts. The N-terminal 598 amino acid region of Xenopus RecQ4 (N598), which lacks a central helicase domain and a downstream C-terminal region, was added to the extracts and its effect on the joining of DNA ends was analyzed. We found that N598 inhibited the joining of linearized DNA ends in the extracts. In addition, N598 inhibited DSB-induced chromatin binding of Ku70, which is essential for NHEJ, while the DSB-induced chromatin binding of the HR-associated proteins, replication protein A (RPA) and Rad51, increased upon the addition of N598. These results suggest that RecQ4 possibly influences the choice of the DSB repair pathway by influencing the association of the Ku heterodimer with the DNA ends.

[Botulism: structure and function of botulinum toxin and its clinical application].

Clostridium botulinum produces seven immunological distinct poisonous neurotoxins, A to G, with molecular masses of approximately 150kDa. In acidic foods and culture fluid, the neurotoxins associate with non-toxic components, and form large complexes designated progenitor toxins. The progenitor toxins are found in three forms named LL, L, and M. These neurotoxins and progenitor toxins were purified, and whole nucleotide sequences of their structure genes were determined. In this manuscript, the structure and function of these toxins, and the application of these toxins to clinical usage have been described.

[Health-related quality of life factor in chronic hemodialysis patients].

AIM: The purpose of this study was to investigate the related factors of the health-related quality of life (HRQOL) measured by KDQOL-SF version 1.3 Japanese version) in chronic hemodialysis patients. METHODS: Using a cross-sectional survey design, we hand-delivered a self-administered questionnaire to the chronic hemodialysis patients and finally obtained 67 subjects' data to analyze. The response rate was 65.7%. Among the related factors, disease/dialysis-related factors and rehabilitation-related factors in addition to demographic factors were examined. The HRQOL was divided into a physical component summary (PCS) and a mental component summary (MCS). RESULTS: Multiple linear regression analysis revealed that the independent factors related to PCS were symptom score, serum albumin level, patients' satisfaction with dialysis care, and the work status. These four factors could explain 60% of PCS variance (adjusted R2 = 0.601). The independent factors related to MCS were revealed to be quality of social interaction and understanding of effectiveness of self-exercise. These two factors could explain only a quarter of MCS variance (adjusted R 2 = 0.223). CONCLUSION: These results suggest that highly satisfactory care of dialysis, improvement of dialysis-related symptoms, and good nutritional management are important for improving HRQOL in chronic hemodialysis patients, and that the promotion of social participation and interpersonal relationships as well as a positive attitude to self-exercise may lead to a beneficial outcome of rehabilitation for chronic hemodialysis patients.

[A longitudinal study of cognitive function and the relationship between cognition and activities of daily living in the elderly].

AIM: To describe fundamental cognitive function and change in the elderly and examine interaction between cognition and ADL. METHODS: We investigated the mental and physical condition of 12,140 persons aged 65 years or over in 2000 and 2002 according to the Eligibility Survey Questionnaire for Long-term Care Insurance. The percentage correct and correlation coefficients of six items in the Questionnaire concerning "Understanding" : "Understands daily activities", "Answers date of birth and age", "Remembers what the subject did before interview", "Says own name", "Knows what season it is now", "Knows the place where the subject is" were determined. The interaction between these six items and ADL were also examined. RESULTS: The percentage correct of "name" was .89, "date of birth and age" .78, "place" .75, "season" .66, "daily activities" .59, "Remembers before interview" .58. The item with high percentages of correct answer in 2000 higher tended to remain high in 2002. Those who were not impaired physically but unable to understand cognitive items tended to require significantly more support for ADL such as "Dressing and undressing", and "Personal hygiene", "Taking medication". CONCLUSION: The percentage correct of each item was considered to be associated with a classical model of memory process: encoding, retention and retrieval. It seemed to require the whole memory process to "Understand daily activities" and "Remember before interview", since the contents were changeable. On the other hand, "name" and "date of birth and age" were relatively well preserved, since these items were encoded and stored in the early stage of life and retrieved repeatedly. "Place" and "Season" were between these two groups.

Sapporo Fitness Club Trial (SFCT)--design, recruitment and implementation of a randomized controlled trial to test the efficacy of exercise at a fitness club for the reduction of cardiovascular risk factor--.

BACKGROUND: The annual health check followed by lifestyle recommendations has long been the standard national strategy to improve cardiovascular disease (CVD) risk factors in Japan. Exercise at fitness clubs, now widely accessible in major cities, has a novel appeal as a strategy with the additive effect of CVD risk reduction. The Sapporo Fitness Club Trial (SFCT) is a randomized controlled trial to compare the efficacy of the national standard alone (control) with the standard plus exercise at a fitness club (intervention) for the reduction of CVD risk factors. METHODS: The SFCT has recruited and randomized 561 relatively inactive overweight men and women, aged 40-85 years, with elevated levels of 2 or more of the following: systolic blood pressure, fasting blood glucose, and low-density lipoprotein cholesterol. The intervention group was required to exercise at a fitness club 2-4 times per week. At the end of 6 months, risk factors, aerobic capacity, health-related quality of life measures, and adverse effects are to be compared. CONCLUSION: The SFCT is expected to have a major impact in Japan on public health recommendations on exercise for the reduction of lifestyle-related disease.

Werner and Bloom helicases are involved in DNA repair in a complementary fashion.

Werner syndrome (WS) is a recessive disorder characterized by premature senescence. Bloom syndrome (BS) is a recessive disorder characterized by short stature and immunodeficiency. A common characteristic of both syndromes is genomic instability leading to tumorigenesis. WRN and BLM genes causing WS and BS, encode proteins that are closely related to the RecQ helicase. We produced WRN-/-, BLM-/- and WRN(-/-)/BLM(-/-) mutants in the chicken B-cell line DT40. WRN-/- cells showed hypersensitivities to genotoxic agents, such as 4-nitroquinoline 1-oxide, camptothecin and methyl methanesulfonate. They also showed a threefold increase in targeted integration rate of exogenous DNAs, but not in sister chromatid exchange (SCE) frequency. BLM-/- cells showed hypersensitivities to the genotoxic agents as well as ultraviolet (UV) light, in addition to a 10-fold increase in targeted integration rate and an 11-fold increase in SCE frequency. In WRN(-/-)/BLM(-/-) cells, synergistically increased hypersensitivities to the genotoxic agents were observed whereas both SCE frequencies and targeted integration rates were partially diminished compared to the single mutants. Chromosomal aberrations were also synergistically increased in WRN(-/-)/BLM(-/-) cells when irradiated with UV light in late S to G(2) phases. These results suggest that both WRN and BLM may be involved in DNA repair in a complementary fashion.