Generation of a novel immunodeficient mouse model of Mucopolysaccharidosis type IIIA to test human stem cell-based therapies.

Mucopolysaccharidosis Type IIIA (MPSIIIA) is a rare inherited lysosomal storage disease caused by mutations in the SGSH gene. This genetic variation results in the deficiency of the N-sulfoglucosamine sulfohydrolase enzyme, preventing the breakdown of heparan sulfate within lysosomes. The progressive accumulation of partially degraded substrate ultimately leads to brain pathology, for which there is currently no approved treatment. An established MPSIIIA mouse model has proved to be a vital asset to test several brain-targeting strategies. Nonetheless, the assessment of human stem cell-based products, an emerging research field, necessitates the use of an immunocompromised xenogeneic disease model. In the present study, we addressed this issue by generating a highly immunodeficient mouse model of MPSIIIA (NOD/SCID/GammaC chain null-MPSIIIA) through five generations of crossing an established MPSIIIA mouse model and a NOD/SCID/GammaC chain null (NSG) mouse. The immune system composition, behavioural phenotype and histopathological hallmarks of the NSG-MPSIIIA model were then evaluated. We demonstrated that NSG-MPSIIIA mice display compromised adaptive immunity, ultimately facilitating the successful engraftment of human iPSC-derived neural progenitor cells in the brain up to three months post-delivery. Furthermore, female NSG-MPSIIIA exhibit spatial working memory deficits and hyperactive behaviour, similar to MPSIIIA mice, which usually manifest around 5 months of age. NSG-MPSIIIA mice also developed primary disease-related neuropathological features in common with the MPSIIIA model, including lysosomal enlargement with storage of excess sulphated heparan sulphate and increased gliosis in several areas of the brain. In the future, the NSG-MPSIIIA mouse model holds the potential to serve as a valuable platform for evaluating human stem-cell based therapies for MPSIIIA patients.

A histopathological review of gynaecological malignancies in Katsina state North-Western Nigeria.

Background: Gynaecological cancers, which affect the female genital tract, constitute a significant public health problem, especially in developing countries. Some of these malignancies have known aetiology and premalignant stages making them preventable. Understanding the burden of gynaecological malignancies in our environment will provide baseline information and help form strategies for their control. Aim: To describe the histological subtypes of gynaecological cancers, their frequency and age distribution trends in Katsina State over the 10-year study period. Methods: This was a 10-year retrospective cross-sectional multicenter study of all histologically diagnosed gynaecological cancer cases seen from 1st January 2012 to 31st December 2021 at Federal Teaching Hospital Katsina, General Hospital Katsina and General Amadi Rimi Specialist Hospital Katsina. Data for this study were extracted from departmental record registers of the pathology laboratories of the corresponding hospitals whose laboratories provide pathology services to the State. Cancer distribution over the years was sorted based on the primary site of diagnosis, histological diagnosis and age. Data were analysed using Statistical Package for Social Science version 28 and results were presented in tables and charts. Results: Two thousand three hundred and fifty-nine cancers were seen over the 10-year study period. Of these cases, 58.4% (n = 1,378) were females. Gynaecological malignancies accounted for 18.7% (441/2,359) of all cancers and 32.0% (441/1,378) of all female cancers. The highest frequency of gynaecological cancers was seen in women who were within the age groups of 40-49 and 50-59, and the lowest was seen in women who were ≥90 years old. The mean age was 48.9 ± 14.9 years. The most common site of gynaecological malignancies was the cervix uteri (n = 262, 59.4%) followed by the ovary (n = 106, 24.0%). Other sites in descending order were corpus uteri (n = 29, 6.6%), vulva (n = 9, 2.0%) and vagina (n = 2, 0.5%). The most common histo-morphologic subtypes were large-cell keratinizing squamous cell carcinoma in the cervix, large-cell non-keratinizing squamous cell carcinoma in the cervix and cystadenocarcinoma in the ovary. Choriocarcinoma was found in 33 cases (7.5%). Conclusion: This study demonstrated the various histotypes of gynaecological malignancies and their trends in Katsina state. The leading cancer was found to be cervical cancer which is mainly preventable. It is hoped that data from this study will provide a basis for making and implementing policies and strategies to lessen the problems of gynaecological malignancies through regular screening programs, especially for cervical cancer and accepting human papilloma virus (HPV) vaccination take-up.

Human papillomavirus serotypes and determinants among women with invasive cervical cancer in Katsina state, Northwest-Nigeria: a multicentre study.

Background: Cervical cancer is the leading cause of gynaecological cancer death among women in developing countries and the most preventable of all gynaecological cancers as its infectious aetiological agent, human papillomavirus (HPV), is known. The knowledge of HPV serotype distribution in a sub-region is key to the implementation of an appropriate HPV vaccination programme. Aim: To assess the prevalence of HPV-DNA, serotypes and risk-determinants among women with invasive cervical cancer (ICC) in Katsina State, Northwestern Nigeria. Methods: This was a cross-sectional, multicenter study involving Federal Teaching Hospital Katsina, General Hospital Katsina and Turai Yar'adua Maternal and Child Hospital Katsina, Nigeria. Sixty-three women with histologically confirmed cervical cancer who fulfilled the criteria were recruited into the study. Tissue blocks with a confirmed diagnosis of ICC were taken to DNA Labs Kaduna for HPV-deoxyribonucleotide acid detection and typing. An interviewer-administered questionnaire developed for the study was used to obtain socio-demographic, reproductive characteristics and the other risk factors for HPV acquisition and persistence. Results: The HPV-positivity rate in ICC was 95.5% while the prevalence of high-risk HPV (Hr-HPV)-DNA in the specimen was 54.6% with 13 HPV-serotypes detected, 9 Hr-HPV types (16,18,31,33,35,45,51,56,82) and 4 low-risk HPV types (6,44,81,89). The most commonly detected HPV serotype among women with a single HPV infection was HPV 81 (40.9%) followed by HPV 16 (28.8%). However, HPV 16 was the most common serotype among those with multiple HPV infections. Prevalence of other detected serotypes were HPV 31 (24.2%), 33 (24.2%), HPV 18 (10.6%), HPV 35 (3.0%), HPV 45 (9.1%), HPV 44 (1.5%), HPV 51 (3.0%), HPV 56 (3.0%), HPV 82 (1.5%), HPV 89 (1.5%) and HPV 6 (1.5%). Forty-four out of 63 women (69.8%) had a single HPV infection, 19 (30.2%) had multiple HPV infections and 15 (24.3%) were co-infected with HPV 16/31/33. There was a statistically significant association between HPV 16 and squamous cell carcinoma (SCC). Conclusion: The study demonstrates a prevalence of HPV-DNA as 95.5% among women with ICC. The most commonly detected HPV serotype was HPV 81 seen in 41% which was an uncommon finding. Furthermore, statistically significant associations between HPV serotypes 16 and 82 with SCC were detected.

An Assessment of Ovarian Cancer Histotypes Across the African Diaspora.

OBJECTIVE: Ovarian cancer in Black women is common in many West African countries but is relatively rare in North America. Black women have worse survival outcomes when compared to White women. Ovarian cancer histotype, diagnosis, and age at presentation are known prognostic factors for outcome. We sought to conduct a preliminary comparative assessment of these factors across the African diaspora. METHODS: Patients diagnosed with ovarian cancer (all histologies) between June 2016-December 2019 in Departments of Pathology at 25 participating sites in Nigeria were identified. Comparative population-based data, inclusive of Caribbean-born Blacks (CBB) and US-born Blacks (USB), were additionally captured from the International Agency for Research on Cancer and Florida Cancer Data Systems. Histology, country of birth, and age at diagnosis data were collected and evaluated across the three subgroups: USB, CBB and Nigerians. Statistical analyses were done using chi-square and student's t-test with significance set at p<0.05. RESULTS: Nigerians had the highest proportion of germ cell tumor (GCT, 11.5%) and sex-cord stromal (SCST, 16.2%) ovarian cancers relative to CBB and USB (p=0.001). CBB (79.4%) and USB (77.3%) women were diagnosed with a larger proportion of serous ovarian cancer than Nigerians (60.4%) (p<0.0001). Nigerians were diagnosed with epithelial ovarian cancers at the youngest age (51.7± 12.8 years) relative to USB (58.9 ± 15.0) and CBB (59.0± 13.0,p<0.001). Black women [CBB (25.2 ± 15.0), Nigerians (29.5 ± 15.1), and USB (33.9 ± 17.9)] were diagnosed with GCT younger than White women (35.4 ± 20.5, p=0.011). Black women [Nigerians (47.5 ± 15.9), USB (50.9 ± 18.3) and CBB (50.9 ± 18.3)] were also diagnosed with SCST younger than White women (55.6 ± 16.5, p<0.01). CONCLUSION: There is significant variation in age of diagnosis and distribution of ovarian cancer histotype/diagnosis across the African diaspora. The etiology of these findings requires further investigation.