Biology subjects

Obonyo, M.

Publications and source records attributed to Obonyo, M..

7 recordsLinked to original sources

bioRxiv2025

Gastric cancer treatment target identified from an accelerated Helicobacter-induced gastric cancer mouse model

Helicobacter pylori (H. pylori) infection and consequent inflammation leads to gastric cancer (GC). Despite the prevalence of this bacterium and availability of genomic data, targeted therapies for GC are still early in development. Previously in our accelerated Helicobacter-induced gastric cancer mouse model we identified several differentially expressed genes (DEGs), including PSMB8 (proteasome subunit beta type 8, also called LMP7); one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. We observed elevated expression of PSMB8 in our accelerated gastric cancer model, in the human gastric cancer cell line (MKN45), and in gastric cancer patient samples. Moreover, we identified carfilzomib as a potential drug that targets PSMB8. Therefore, to test its efficacy against gastric cancer, nude mice were subcutaneously implanted with MKN45 derived tumors and treated with carfilzomib, alone or in combination with 5-fluorouracil (5-FU), the standard care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. We observed that carfilzomib retarded tumor growth, inhibited cell proliferation and induced apoptosis. These results strongly suggest that carfilzomib has a robust anti-tumor activity and is a suitable drug candidate for targeted therapy in gastric cancer.

cancer biology↗

bioRxiv2023

Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.

Helicobacter pylori (H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori-induced disease progression. We have established a Helicobacter-induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) with H. felis. Using this model, we report here that that progression of H. felis-induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis-induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-{beta} (TRIF, TrifLps2) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.

cancer biology↗

bioRxiv2020

Microbiome signatures in a fast and slow progressing gastric cancer murine model and their contribution to gastric carcinogenesis

Gastric cancer is the third most common cancer in the world and Helicobacter spp. being one of the main factors responsible for development of cancer. Alongside Helicobacter the microbiota of the stomach mucosa may also play an important role in gastric cancer progression. Previously we had established that MyD88 deficient mice rapidly progressed to neoplasia when infected with H. felis. Thus, in order to assess the role of microbiota in gastric cancer progression we measured the changes in microbial diversity of the stomach in mice with different genotypic backgrounds (Wild type (WT), MyD88 deficient (MyD88-/-), mice deficient in the Toll/IL-1R (TIR) domain-containing adaptor-inducing interferon-{beta} (TRIF, Triflps2), and MyD88 and Trif deficient (MyD88-/- and Trif-/-)double knockout (DKO) mice), both in uninfected and Helicobacter infected mice and its correlation of these changes with gastric cancer progression. We observed that there was an overall reduction in microbial diversity post infection with H. felis across all genotypes. Campylobacterales were observed in all infected mice, with marked reduction in abundance at 3 and 6 months in MyD88-/- mice. This low abundance of H. pylori could facilitate dominance of other organisms of microbiome like Lactobacilliales. A sharp increase in Lactobacilliales in infected MyD88-/- and DKO mice at 3 and 6 months was observed as compared to Trif-/- and WT mice suggesting its possible role in gastric cancer progression. This was further reinforced upon comparison of Lactobacillus ratio with histological data suggesting that Lactobacillales is closely associated with Helicobacter infection and gastric cancer progression. Thus, this study firstly suggests that difference in genotypes could define the stomach microbiome and make it more susceptible to development of gastric cancer upon Helicobacter infections. Secondly the increase in Lactobacillales could contribute to faster development of gastric cancer and serve as a probable bio marker for fast progressing form of gastric cancer.

cancer biology↗

bioRxiv2020

Leptospira spp. seroprevalence in humans involved in a cross-sectional study in Garissa and Tana River Counties, Kenya

IntroductionLeptospirosis is a neglected bacterial zoonotic infection caused by spirochetes of Leptospira genus. Humans get infected through direct or indirect contact with urine of infected animals or environment. It accounts for more than 300,000 severe cases annually worldwide with case fatality rates of over 30%. Costs of diagnosis and treatment for human and animals, disruption of international trade of animals and products, reduced productivity and reproductivity in animals constitute economic importance. In Kenya, leptospirosis burden is significant but under-diagnosis and under-reporting affects the awareness of the disease. This study aimed to determine and compare the sero-prevalence and factors associated with Leptospira spp. in the two counties. MethodsWe conducted a cross-sectional study that involved apparently healthy people of at least 5 years of age in randomly selected households in Garissa and Tana River Counties. Blood samples were collected and tested for Leptospira spp antibodies using IgM ELISA. Standardized structured questionnaires were administered to collect socio-demographic and exposure information. We calculated frequencies and proportions for categorical variables and odds ratios (OR) and 95% confidence interval (CI) to evaluate association between sero-positivity and exposure factors. We used Wilcoxon test to evaluate statistical difference in sero-positivity for continuous variables and calculated test statistic (H) and p-value. ResultsA total of 952 subjects were recruited into the study - these included 482 persons from Garissa and 470 from Tana River. The overall sero-prevalence was 26% [(244/952); (CI: 23% to 29%)]. Garissa County had significantly higher Leptospira spp. seroprevalence (31%, n = 147; CI: 27% to 35%) compared to Tana River County (21 %, n = 97; CI: 17% to 25%). Being a female (OR=1.6, CI: 1.2-2.2) and engaging in pastoralism (OR=2.7, CI: 1.8-3.9) were significantly associated with higher odds of Leptospira spp. seropositivity compared to being a male or working in irrigated areas. The mean altitude of residence of sero-positive patients was 73m {+/-} 21 SD (standard deviation) above sea level and that for sero-negative was 80m {+/-} 22 SD (H=35, p-value = 0.00). ConclusionThis study determined the seroprevalence and risk factors for Leptospira spp. exposure in Garissa and Tana River Counties, Kenya. Females in pastoral communities experience high burden of the disease. Enhanced surveillance in humans and animals and further research is required to understand the complex and multifactorial drivers of leptospirosis transmission in the two Counties.

microbiology↗

bioRxiv2020

Early detection of biomarkers for circulating tumor cells in Bone marrow and Peripheral blood in a fast-progressing gastric cancer model.

Helicobacter pylori poses one of the greatest risks for development of gastric cancer. We previously established a crucial role for myeloid differentiation primary response 88 (MyD88) in the regulation of Helicobacter-induced gastric cancer. Mice deficient in Myd88 rapidly progressed to neoplasia when infected with H. felis, a close relative of H. pylori. For this study we examined circulating tumor cells (CTCs) by measuring expression of cytokeratins, epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) markers in in the bone marrow and peripheral blood of gastric cancer models we termed fast (Myd88-/-)- and slow (WT)-"progressors". We detected cytokeratins CK8/18 as early as 3 months post infection in the fast "progressors". In contrast, cytokeratins were not detected in slow "progressor" gastric cancer model even after 7 months post infection. Expression of MUC1 was observed in both bone marrow and peripheral blood at different time points suggesting its role in gastric cancer metastasis. Snail, Twist and ZEB were expressed at different levels in bone marrow and peripheral blood. Expression of these EMT markers suggests manifestation of cancer metastasis in the early stages of disease development. Lgr5, CD44 and CD133 were the most prominent CSC markers detected. Detection of CSC and EMT markers along with cytokeratins does reinforce their use as biomarkers for gastric cancer metastasis. This early detection of markers suggests that CTCs leave primary site even before cancer is well established. Thus, cytokeratins, EMT, and CSCs could be used as biomarkers to detect aggressive forms of gastric cancers. This information will be important in stratifying patients for treatment before the onset of severe disease characteristics.

cancer biology↗

bioRxiv2019

Factors associated with cholera outbreaks, Nairobi County, July 2017: a case control study

BackgroundCholera affects 1.3-4 million people globally and causes 21000-143,000 deaths annually. Nairobi County in Kenya reported cholera cases since April 2017. We investigated to identify associated factors and institute control measures.\n\nMethodsWe reviewed the line-list of patients admitted at the Kenyatta National referral Hospital, Nairobi and performed descriptive epidemiology. We carried out a frequency-matched case control study, using facility-based cases and community controls. We defined a case as acute onset of watery diarrhoea of at least >3 stools/24hours with or without vomiting in person of any age, admitted in Kenyatta National Hospital as from July 1st, 2017. We calculated odds ratios and their respective 95% confidence intervals. We also took water samples at water reservoirs, distribution and consumer points, and made observation on hygiene and sanitation conditions in the community.\n\nResultsWe reviewed 71 line-listed cases; median age 30 years (range 2-86 years); 45 (63%) were male. First case was admitted on 14th April 2017. Culture was performed on 44 cases, 30 (68%) was positive for Vibrio cholerae, biotype El-Tor, serotype Ogawa. There were 2 deaths (case fatality ratio 2.8%). Age-group [≥]25 years was most affected. Drinking unchlorinated water (aOR 14.57, 95% CI 4.44-47.83), eating in public places (aOR 9.45, 95% CI 3.07-29.12) sourcing water from non-Nairobi city water company source (aOR 4.92, 95% CI 1.56-15.52) and having drank untreated water in the previous week before the outbreak (aOR 3.21, 95% CI 1.12-9.24) were independently associated with being a case in the outbreak. Out of 28 water samples, 4 (14%) had >180 coliforms/100mls; all were at consumer points.\n\nConclusionPoor water quality and sanitation were responsible for this outbreak. We recommended adequate, clean water supply to unplanned settlements in Nairobi County, as well education of residents on water treatment at the household level.\n\nAuthor summaryCholera, a disease causing outbreaks in areas with low standards of hygiene and sanitation has afflicted humans for millennia. It is caused by a bacterium, Vibrio Cholerae, transmitted mainly through water contaminated by faecal matter. The resultant disease is acute watery diarrhoea, which causes death rapidly due to dehydration and shock. Virtually brought under control in the developed world due to improvements in hygiene, the disease still ravages many communities in low and middle income countries, as well as regions affected by conflict or natural disasters. In outbreak situations, rapid response in water treatment, sanitation improvement and setting up of cholera treatment centres for rehydration therapy reduces impact and saves lives. Long-term control can only be achieved through sustainable improvements in sanitation and standards of living. Case control studies in outbreak situations provide quick, actionable information to public health specialists during outbreak response. This study provides a cholera outbreak investigation in an urban informal settlement setting; the approach reported here can guide in outbreak investigations and response in similar settings globally.

epidemiology↗

bioRxiv2019

Cases of Cutaneous Leishmaniasis in a peri-urban settlement in Kenya, 2016

BackgroundCutaneous Leishmaniasis is a neglected tropical disease caused by a protozoan and transmitted by sand-fly bite. Following reports of a possible outbreak of cutaneous leishmaniasis in 2016, we conducted a review of hospital records and a follow up case control study to determine the magnitude of the disease, characterize the cases and identify factors associated with the disease in Gilgil, a peri-urban settlement in Central Kenya. MethodsWe reviewed hospital records, conducted active case search in the community and carried out a case-control study. Medical officers in the study team made clinical diagnosis of cutaneous leishmaniasis cases based on presence of a typical skin ulcer. We enrolled 58 cases matched by age and residence to 116 controls in a case control study. We administered structured questionnaires and recorded environmental observations around homes of cases and controls. Simple proportions, means and medians were calculated for categorical data and continuous data respectively. Logistic regression models were constructed for individual, indoor and outdoor factors associated with the outbreak. ResultsWe identified 255 suspected cases and one death; Females constituted 56% (142/255), median age of the cases was 7 years (IQR 14). Cases were clustered around Gitare (28.6%, 73/255) and Kambi-Turkana (14%, 36/255) with seasonal peaks between June-November. Among individual factors, staying outside the residence in the evening after sunset (OR 4.1, CI 1.2-16.2) and occupation involving visiting forests (OR 4.56, CI 2.04-10.22) had significant associations with disease. Sharing residence with a cutaneous leishmaniasis patient (OR 14.4, CI 3.8-79.3), a house with alternative roofing materials (OR 7.9, CI 1.9-45.7) and residing in a house with cracked walls (OR 2.3, CI 1.0-4.9) were significant among indoor factors while sighting rock hyraxes near residence (OR 5.3, CI 2.2-12.7), residing near a forest (OR 7.8, CI 2.8-26.4) and living close to a neighbour with cutaneous leishmaniasis (OR 6.8, CI 2.8-16.0) had increased likelihood of disease. Having a cultivated crop farm surrounding the residence (OR 0.1, CI 0.0-0.4) was protective. Conclusions/SignificanceThis study reveals the large burden of cutaneous leishmaniasis in Gilgil. There is strong evidence for both indoor and outdoor patterns of disease transmission. Occupations and activities that involve visiting forests or residing near forests and sharing a house or neighbourhood with a person with CL were identified as significant exposures of the disease. The role of environmental factors and wild mammals in disease transmission should be investigated further Author summaryLeishmaniasis is a group of diseases caused by a protozoa (Leishmania) and affects humans and other mammals following the bite of an infected sand-fly. Cutaneous form of the disease (cutaneous leishmaniasis) is considered a neglected tropical disease mainly affecting the poor destabilized or migrant populations in rural areas. Recently, the disease has expanded its geographical range and invaded previously non-endemic areas including areas surrounding large urban centres that are experiencing human population influx leading to multiple localised disease outbreaks. In this paper, we report findings of a study we conducted to determine the burden and factors promoting the spread of cutaneous leishmaniasis in a peri-urban settlement in Kenya. Our results indicate a high burden of cutaneous leishmaniasis in this area and an association of the disease with several groups of factors at individual, indoor and outdoor environments. Many cases of cutaneous leishmaniasis were linked to activities that involved visiting the forested areas around homes, underpinning the significance of human activity in forests in these areas in spread of the disease.

epidemiology↗