PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression

Population and Geospatial Risks of Vaccine-Derived Poliovirus Type-2 in the Democratic Republic of the Congo

Poliovirus, once a global pandemic is now in its endgame eradication stages. Currently, wild poliovirus type 2 and 3 have been declared eradicated by the World Health Organization (WHO) and wild type 1 is circulating in just two remaining countries. As the Sabin oral polio vaccine utilizes a live attenuated strain of poliovirus, in 2012 the WHO General Assembly released a strategic plan for polio eradication that called for the eventual removal of the oral polio vaccine. In April 2016, the WHO coordinated a global switch day where trivalent oral polio vaccines containing poliovirus type 2 were replaced with bivalent vaccines containing polio types 1 and 3 only. Since then, vaccine-derived poliovirus infections in the Democratic Republic of the Congo (DRC) have risen as polio vaccine coverage rates, and specifically rates against serotype 2, have fallen. This dissertation serves to contribute towards polio eradication efforts in the DRC by describing the landscape of childhood vaccination against poliovirus in a vaccine-derived poliovirus endemic region and quantify how the key vaccine intervention, supplementary immunization campaigns, contribute to improving vaccine coverage. Chapter 1 provides a summary of the pathology of polio and its pandemic history, as well as the WHO endgame strategic plan and policies and the landscape of polio in DRC. Chapter 2 quantifies community immunity against poliovirus and risk factors for under immunization among children under five in an outbreak prone region of southeastern DRC. Chapter 3 explores how repeated immunization interventions impacts community vaccine coverage and uses propensity score weighting to compare a gold standard biomarker for vaccination to material recall collected via questionnaire. Chapter 4 explores the spatial point process of vaccine-derived poliovirus cases and how spatial access to health care can impact under-vaccination. This dissertation finds that ultimately, access to vaccine in the DRC is an enduring issue related to challenges associated with DRC’s resource-poor health system and systemic issues with infrastructure. Vaccine immunization campaigns do improve community immunity, but likely are not providing adequate coverage to halt the spread of vaccine-derived polio viruses. Addressing the limitations of the current vaccine strategy head on can help move the DRC closer to polio eradication

Population and Geospatial Risks of Vaccine-Derived Poliovirus Type-2 in the Democratic Republic of the Congo

Poliovirus, once a global pandemic is now in its endgame eradication stages. Currently, wild poliovirus type 2 and 3 have been declared eradicated by the World Health Organization (WHO) and wild type 1 is circulating in just two remaining countries. As the Sabin oral polio vaccine utilizes a live attenuated strain of poliovirus, in 2012 the WHO General Assembly released a strategic plan for polio eradication that called for the eventual removal of the oral polio vaccine. In April 2016, the WHO coordinated a global switch day where trivalent oral polio vaccines containing poliovirus type 2 were replaced with bivalent vaccines containing polio types 1 and 3 only. Since then, vaccine-derived poliovirus infections in the Democratic Republic of the Congo (DRC) have risen as polio vaccine coverage rates, and specifically rates against serotype 2, have fallen. This dissertation serves to contribute towards polio eradication efforts in the DRC by describing the landscape of childhood vaccination against poliovirus in a vaccine-derived poliovirus endemic region and quantify how the key vaccine intervention, supplementary immunization campaigns, contribute to improving vaccine coverage. Chapter 1 provides a summary of the pathology of polio and its pandemic history, as well as the WHO endgame strategic plan and policies and the landscape of polio in DRC. Chapter 2 quantifies community immunity against poliovirus and risk factors for under immunization among children under five in an outbreak prone region of southeastern DRC. Chapter 3 explores how repeated immunization interventions impacts community vaccine coverage and uses propensity score weighting to compare a gold standard biomarker for vaccination to material recall collected via questionnaire. Chapter 4 explores the spatial point process of vaccine-derived poliovirus cases and how spatial access to health care can impact under-vaccination. This dissertation finds that ultimately, access to vaccine in the DRC is an enduring issue related to challenges associated with DRC’s resource-poor health system and systemic issues with infrastructure. Vaccine immunization campaigns do improve community immunity, but likely are not providing adequate coverage to halt the spread of vaccine-derived polio viruses. Addressing the limitations of the current vaccine strategy head on can help move the DRC closer to polio eradication

Investigating a Syndromic Surveillance Signal with Complimentary Data Systems

In early June, the New York City syndromic surveillance system detected five signals in sales of over-the-counter antidiarrheal medications. To determine if this increase reflected a concerning cluster of diarrheal illness, we examined multiple communicable disease surveillance data systems. After further investigation of syndromic and other systems, we determined that findings possibly reflected sales promotions but did not suggest increased diarrheal illness in NYC

Correction: Human T-cell lymphotropic virus type 1 transmission dynamics in rural villages in the Democratic Republic of the Congo with high nonhuman primate exposure

[This corrects the article DOI: 10.1371/journal.pntd.0008923.]

Human T-cell lymphotropic virus type 1 transmission dynamics in rural villages in the Democratic Republic of the Congo with high nonhuman primate exposure.

The Democratic Republic of the Congo (DRC) has a history of nonhuman primate (NHP) consumption and exposure to simian retroviruses yet little is known about the extent of zoonotic simian retroviral infections in DRC. We examined the prevalence of human T-lymphotropic viruses (HTLV), a retrovirus group of simian origin, in a large population of persons with frequent NHP exposures and a history of simian foamy virus infection. We screened plasma from 3,051 persons living in rural villages in central DRC using HTLV EIA and western blot (WB). PCR amplification of HTLV tax and LTR sequences from buffy coat DNA was used to confirm infection and to measure proviral loads (pVLs). We used phylogenetic analyses of LTR sequences to infer evolutionary histories and potential transmission clusters. Questionnaire data was analyzed in conjunction with serological and molecular data. A relatively high proportion of the study population (5.4%, n = 165) were WB seropositive: 128 HTLV-1-like, 3 HTLV-2-like, and 34 HTLV-positive but untypeable profiles. 85 persons had HTLV indeterminate WB profiles. HTLV seroreactivity was higher in females, wives, heads of households, and increased with age. HTLV-1 LTR sequences from 109 persons clustered strongly with HTLV-1 and STLV-1 subtype B from humans and simians from DRC, with most sequences more closely related to STLV-1 from Allenopithecus nigroviridis (Allen's swamp monkey). While 18 potential transmission clusters were identified, most were in different households, villages, and health zones. Three HTLV-1-infected persons were co-infected with simian foamy virus. The mean and median percentage of HTLV-1 pVLs were 5.72% and 1.53%, respectively, but were not associated with age, NHP exposure, village, or gender. We document high HTLV prevalence in DRC likely originating from STLV-1. We demonstrate regional spread of HTLV-1 in DRC with pVLs reported to be associated with HTLV disease, supporting local and national public health measures to prevent spread and morbidity

Nutritional Status Link with Polioseronegativity Among Children from Poliomyelitis Transmission High-Risk Area of the Democratic Republic of the Congo (DRC).

BACKGROUND: Malnutrition is identified as a risk-factor for insufficient polioseroconversion in the context of a vaccine-derived polio virus (VDPV) outbreak prone region. To assess the prevalence of malnutrition and its link to poliovirus insufficient immunity, a cross-sectional household survey was conducted in the regions of Haut- Lomami and Tanganyika, DRC. METHODS: In March 2018, we included 968 healthy children aged 6 to 59 months from eight out of 27 districts. Selection of study locations within these districts was done using a stratified random sampling method, where villages were chosen based on habitat characteristics identified from satellite images. Consent was obtained verbally in the preferred language of the participant (French or Swahili) by interviewers who received specific training for this task. Furthermore, participants contributed a dried blood spot sample, collected via finger prick. To assess malnutrition, we measured height and weight, applying WHO criteria to determine rates of underweight, wasting, and stunting. The assessment of immunity to poliovirus types 1, 2, and 3 through the detection of neutralizing antibodies was carried out at the CDC in Atlanta, USA. RESULTS: Of the study population, we found 24.7% underweight, 54.8% stunted, and 15.4% wasted. With IC95%, underweight (OR=1.50; [1.11-2.03]), and the non-administration of vitamin A (OR=1.96; [1.52-2.54]) were significantly associated with seronegativity to polioserotype 1. Underweight (OR=1.64; [1.20-2.24]) and the non-administration of vitamin A (OR=1.55; [1.20-2.01]) were significantly associated with seronegativity to polioserotype 2. Underweight (OR=1.50; [1.11-2.03]), and the non-administration of vitamin A (OR=1.80. [1.38-2.35]) were significantly associated with seronegativity to polioserotype 3. Underweight (OR=1.68; IC95% [1.10-2.57]) and the non-administration of vitamin A (OR=1.82; IC95% [1.30-2.55]) were significantly associated with seronegativity to all polioserotypes. CONCLUSION: This study reveals a significant association between underweight and polioseronegativity in children. In order to reduce vaccine failures in high-risk areas, an integrated approach by vaccination and nutrition programs should be adopted