Determination of maximum tolerated dose and toxicity of Inauhzin in mice

AbstractReactivating the tumor suppressor p53 offers an attractive strategy for developing cancer therapy. We recently identified Inauhzin (INZ) as a novel non-genotoxic p53-activating compound. To develop INZ into a clinically applicable anticancer drug, we have initiated preclinical toxicity studies. Here, we report our study on determining the maximum tolerated dose (MTD) of INZ analog, Inauhzin-C (INZ (C)), following intraperitoneal (i.p.) administration (Phase A) and its toxicity following i.p. administration over a period of 5-day dosing plus 2-day recovery (Phase B) in CD-1 mice. The Phase A study showed that the MTD of INZ (C) is 200mg/kg for female and 250mg/kg for male, respectively. The Phase B study showed that the administration of INZ (C) via 5-day consecutive i.p. injection is tolerated by female CD-1 mice at all dose levels tested from 50mg/kg to 120mg/kg without significant changes in biochemical and pathological parameters in the animals. Together, these results indicate that our previously determined effective dose of INZ at 30–60mg/kg via i.p. is quite safe to mice, and imply that this compound have the features worthy for further development into a clinically applicable drug

Hepatoblastoma in Adult: Review of the Literature

This study is to review and retrieve data on adult hepatoblastoma (HB) from English literatures in order to gain a better understanding of this disease. We performed Medline, PubMed (from January 1966 to February 2008), and library searches (National Science and Technology Library, Beijing, China, and Wenzhou Medical College Library, from January 1980 to February 2008) using the key words hepatoblastoma in adult, hepatic tumor, hepatoblastoma and adult. Previously reported HB cases were collected and published reviews were also examined. Fifteen cases that met the search criteria were selected. Review of the cases revealed a slight female preponderance. The patients' age ranged from 17 to 82, with median age of 70 for male and 27 for female. The survival time ranged from two weeks to 38 months, and the median survival time was 6 months. In the articles reviewed, HB presented with non-specific initial symptoms, and the diagnosis was not identified until the tumor biopsy after operation or autopsy. Completely surgical resection is still the major treatment for patients with HB and is considered as the only chance of a better prognosis. Due to the rareness of HB in adults, the choice of treatment should be radical resection if possible, and combined with chemotherapy as adopted in children. HB in the adult is extremely rare and the pre-operative diagnosis is often overlooked. The prognosis is so poor that the awareness of the condition in the differential diagnosis in liver tumors could be beneficial

The role of IMP dehydrogenase 2 in Inauhzin-induced ribosomal stress

The ‘ribosomal stress (RS)-p53 pathway’ is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. Inosine monophosphate (IMP) dehydrogenase 2 (IMPDH2) is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2

Trends in incidence and mortality of nasopharyngeal carcinoma over a 20–25 year period (1978/1983–2002) in Sihui and Cangwu counties in southern China

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world but is common in southern China. A recent report from the Hong Kong Cancer Registry, a high-risk area for NPC in southern China, showed that incidence rate decreased by 29% for males and by 30% for females from 1980–1999, while mortality rate decreased by 43% for males and 50% for females. Changing environmental risk factors and improvements in diagnosis and treatment were speculated to be the major factors contributing to the downward trend of the incidence and mortality rates of NPC. To investigate the secular trends in different Cantonese populations with different socio-economic backgrounds and lifestyles, we report the incidences and mortality rates from two population-based cancer registries in Sihui and Cangwu counties from 1978–2002. METHODS: Incidence and mortality rates were aggregated by 5-year age groups and 5 calendar years. To adjust for the effect of difference in age composition for different periods, the total and age-specific rates of NPC incidence and mortality rate were adjusted by direct standardization according to the World Standard Population (1960). The Estimated Annual Percentage Change (EAPC) was used as an estimate of the trend. RESULTS: The incidence rate of NPC has remained stable during the recent two decades in Sihui and in females in Cangwu, with a slight increase observed in males in Cangwu from 17.81 to 19.76 per 100,000. The incidence rate in Sihui is 1.4–2.0 times higher during the corresponding years than in Cangwu, even though the residents of both areas are of Cantonese ethnicity. A progressive decline in mortality rate was observed in females only in Sihui, with an average reduction of 6.3% (p = 0.016) per five-year period. CONCLUSION: To summarize, there is great potential to work in the area of NPC prevention and treatment in southern China to decrease NPC risk and improve survival risk rates in order to reduce M:I ratios. Future efforts on effective prevention, early detection and treatment strategies were also discussed in this paper. Furthermore, the data quality and completeness also need to be improved

Detection of STAT2 in early stage of cervical premalignancy and in cervical cancer

AbstractObjectiveTo measure the expression pattern of STAT2 in cervical cancer initiation and progression in tissue sections from patients with cervicitis, dysplasia, and cervical cancer.MethodsAntibody against human STAT2 was confirmed by plasmids transient transfection and Western blot. Immunohistochemistry was used to detect STAT2 expression in the cervical biopsies by using the confirmed antibody against STAT2 as the primary antibody.ResultsIt was found that the overall rate of positive STAT2 expression in the cervicitis, dysplasia and cervical cancer groups were 38.5%, 69.4% and 76.9%, respectively. The STAT2 levels are significantly increased in premalignant dysplasia and cervical cancer, as compared to cervicitis (P< 0.05). Noticeably, STAT2 signals were mainly found in the cytoplasm, implying that STAT2 was not biologically active.ConclusionsThese findings reveal an association between cervical cancer progression and augmented STAT2 expression. In conclusion, STAT2 increase appears to be an early detectable cellular event in cervical cancer development

A Systematic Review and Meta-Analysis of 19 Randomized Controlled Trials of Iguratimod Combined With Other Therapies for Sjogren’s Syndrome

ObjectiveTo explore the efficacy and safety of Iguratimod intervention in Primary Sjogren’s syndrome (pSS).MethodsMany databases were searched to collect the RCTs. Three independent reviewers extracted data and assessed the quality of the studies based on the Cochrane Handbook. The statistical analysis was done by RevMan 5.3 and STATA. The quality of evidence was evaluated by GRADE tool.ResultsTwenty-nine RCTs with 2258 participants were included in this review. The meta-analysis shows that: iguratimod experiment group can reduce the ESSPRI score (WMD -1.93 [-2.33, -1.52], P&lt;0.00001), ESSDAI score (WMD -1.39 [-1.81, -0.98], P&lt;0.00001), Schirmer’s test (WMD 1.77 [0.85, 2.70], P=0.0002), RF (WMD -5.78 [-7.59, -3.97], P&lt;0.00001), and decrease the ESR level (WMD -7.05 [-9.84, -4.26], P&lt;0.00001). Meanwhile, the summary result showed the addiction of Iguratimod may not increase the adverse events. The adverse events were mainly gastrointestinal discomfort, abnormal liver function, and rash and itching. The quality of evidence of adverse events was moderate. Referring to minimal clinically important difference (MCID), the improvement of ESSPRI is clinically significant, and the improvement of ESSDAI for patients older than 60 years old may be clinically significant.ConclusionBased on current evidence, iguratimod can effectively reduce ESSPRI score, ESSDAI score, Schirmer’s test score and decrease systemic inflammatory response (such as ESR level and RF level) without increasing the probability of adverse events. The recommended course of treatment is at least 12 weeks.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42020220770