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Clear cell renal cell carcinoma (CC-RCC) is the most lethal of all genitourinary cancers. The functional loss of the von Hippel-Lindau (VHL) gene occurs in 90% of CC-RCC, driving cancer progression. The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the library of pharmacologically active compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by small interfering RNA (siRNA) selectively reduced the colony-forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-27632 treatment, whereas downregulation of ROCK2 had no effect. In addition, two other ROCK inhibitors, RKI 1447 and GSK 429286, selectively targeted VHL-deficient CC-RCC. CC-RCC treatment with ROCK inhibitors is cytotoxic and cytostatic based on bromodeoxyuridine (BrdU) assay, propidium iodide (PI) staining and growth curves, and blocks cell migration based on transwell assay. On the one hand, knockdown of hypoxia-inducible factor (HIF) β in the VHL-deficient CC-RCC had a protective effect against Y-27632 treatment, mimicking VHL reintroduction. On the other hand, CC-RCCVHL cells were sensitized to Y-27632 treatment in hypoxia (2% O2). These results suggest that synthetic lethality between ROCK inhibition and VHL deficiency is dependent on HIF activation. Moreover, HIF1α or HIF2α overexpression in CC-RCCVHL cells is sufficient to sensitize them to ROCK inhibition. Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 CC-RCC tumors in mice. Thus, ROCK inhibitors represent potential therapeutics for VHL-deficient CC-RCC.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic form of breast cancer that lacks the estrogen, progesterone and HER2 receptors and is resistant to targeted and hormone therapies. TNBCs express high levels of the transmembrane glycoprotein, complement C1r/C1s, Uegf, Bmp1 (CUB)-domain containing protein 1 (CDCP1), which has been correlated with the aggressiveness and poor prognosis of multiple carcinomas. Full-length CDCP1 (flCDCP1) can be proteolytically cleaved, resulting in a cleaved membrane-bound isoform (cCDCP1). CDCP1 is phosphorylated by Src family kinases in its full-length and cleaved states, which is important for its pro-metastatic signaling. We observed that cCDCP1, compared with flCDCP1, induced a dramatic increase in phosphorylation of the migration-associated proteins: PKCδ, ERK1/2 and p38 mitogen-activated protein kinase in HEK 293T. In addition, only cCDCP1 induced migration of HEK 293T cells and rescued migration of the TNBC cell lines expressing short hairpin RNA against CDCP1. Importantly, we found that only cCDCP1 is capable of dimerization, which can be blocked by expression of the extracellular portion of cCDCP1 (ECC), indicating that dimerization occurs through CDCP1's ectodomain. We found that ECC inhibited phosphorylation of PKCδ and migration of TNBC cells in two-dimensional culture. Furthermore, ECC decreased cell invasiveness, inhibited proliferation and stimulated apoptosis of TNBC cells in three-dimensional culture, indicating that the cCDCP1 dimer is an important contributor to TNBC aggressiveness. These studies have important implications for the development of a therapeutic to block CDCP1 activity and TNBC metastasis.

Background: As countries approach HIV epidemic control, client-centred interventions are necessary to address persistent barriers to HIV prevention, care and treatment. We describe a deep-learning model to rapidly analyse qualitative [...]

Background: The COVID-19 pandemic is associated with increased gender-based violence (GBV) perpetration. However, the COVID-19 response did not prioritize GBV services, negatively impacting post-violence care service access among girls/women in [...]

Background: TB preventive therapy (TPT) among people living with HIV (PLHIV) reduces the risk of developing TB disease. In Fort Portal region, data on TPT outcomes among PLHIV are scarce. [...]

OBJECTIVE: To describe trends and highlight epidemiologic and clinical characteristics of childhood tuberculosis (TB) in the United States. METHODS: All verified TB cases reported to the national TB surveillance system from 1993 to 2001 were included. A child was defined as a person younger than 15 years. RESULTS: A total of 11,480 childhood TB cases were reported. Case rates (TB cases/100,000 population) in all children declined from 2.9 (n = 1663) in 1993 to 1.5 (n = 931) in 2001. Among children, those who were younger than 5 years had the highest rate. California, Texas, and New York accounted for 48% of all childhood TB cases. In 2001, TB case rates were higher for foreign-born (12.2) than US-born children (1.1). Hispanic and non-Hispanic black children accounted for nearly three quarters of all cases. Twenty-four percent of children with TB were foreign-born children, with the largest number originating from Mexico (39.8%), the Philippines (8.6%), and Vietnam (5.7%). Most children had evidence of pulmonary TB disease (78.9%). Among culture-positive cases without previous TB, drug resistance to at least isoniazid was 7.3% and to isoniazid and rifampin was 1.6%. In 1999, 82.9% of children received directly observed therapy for at least part of their treatment and 94.8% completed treatment. CONCLUSIONS: Although the overall TB case number among children is declining in the United States, certain groups of children (eg, younger children, racial and ethnic minorities, foreign-born) are at higher risk for TB. As the United States moves toward the elimination of TB, future efforts should endeavor to prevent all cases of childhood TB. [ABSTRACT FROM AUTHOR]

Background & Aims: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112)., Methods: Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'., Results: A total of 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on drug concentrations., Conclusions: Extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative control drugs for validation of in vitro models of DILI is proposed., Impact and Implications: Prediction of human toxicity early in the drug development process remains a major challenge, necessitating the development of more physiologically relevant liver models and careful selection of drug-induced liver injury (DILI)-positive and -negative control drugs to better predict the risk of DILI associated with new drug candidates. Thus, this systematic study has crucial implications for standardizing the validation of new in vitro models of DILI. By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

During population-based HIV impact assessments (PHIAs), some participants who self-reported testing HIV-positive (PSRP) tested negative in one or more subsequent survey HIV tests. These unexpected discrepancies between their self-reported results and the survey results draw into question the validity of either the self-reported status or the test results. We analyzed PSRP with negative test results aged 15-59 years old using data collected from 2015 to 2021 in 13 countries, assessing prevalence, self-report status, survey HIV status, viral load, rapid tests and confirmatory tests, and answers to follow-up questions (such as years on treatment). Across these surveys, 19,026 participants were PSRP, and 256 (1.3%) of these were concluded to be HIV-negative after additional survey-based testing and review. PSRP determined to be HIV-negative trended higher in countries with a higher HIV prevalence, but their number was small enough that accepting self-reported HIV-positive status without testing would not have significantly affected the prevalence estimates for HIV or viral load suppression. Additionally, using more detailed information for Uganda, we examined 107 PSRP with any negative test results and found no significant correlation with years on treatment or age. Using these details, we examined support for the possible reasons for these discrepancies beyond misdiagnosis and false reporting. These findings suggest that those conducting surveys would benefit from a nuanced understanding of HIV testing among PSRP to conduct surveys ethically and produce high-quality results.

This study compared parenting across four non-Western cultures to test cross-cultural commonality and specificity principles in three aspects: measurement properties, parenting normativeness, and their associations with child outcomes. Both mothers and fathers (N = 1509 dyads) with preschool-aged children (M = 5.00 years; 48% girls) from urban areas of four countries (Malaysia, N = 372; China, N = 441; Turkey, N = 402; and Japan, N = 294) reported on four parenting constructs (authoritative, authoritarian, group harmony socialization, and intrusive control) and their sub-dimensions using modified culturally relevant measures. Teachers reported on children's internalizing, externalizing, and prosocial behaviors. The commonality principle was supported by two sets of findings: (1) full measurement invariance was established for most parenting constructs and sub-dimensions, except that intrusive control only reached partial scalar invariance, and (2) no variations were found in associations between parenting and any child outcomes across cultures or parent gender at the construct level for all four parenting constructs and at the sub-dimensional level for authoritarian and intrusive control sub-dimensions. The specificity principle was supported by the other two sets of findings: (1) cross-cultural differences in parenting normativeness did not follow the pattern of economic development but yielded culture-specific patterns, and (2) at the sub-dimensional level, the authoritative parenting and group harmony socialization sub-dimensions were differently associated with child outcomes across cultures and/or parent gender. The findings suggested that examining specific dimensions rather than broad parenting constructs is necessary to reflect cultural specificities and nuances. Our study provided a culturally-invariant instrument and a three-step guide for future parenting research to examine cross-cultural commonalities/specificities. RESEARCH HIGHLIGHTS: This is the first study to use an instrument with measurement invariance across multiple non-Western cultures to examine the commonality and specificity principles in parenting. Measurement invariance was achieved across cultures for authoritative and authoritarian parenting, group harmony socialization, intrusive control, and their sub-dimensions, supporting the commonality principle. Cross-cultural differences in parenting normativeness did not follow the pattern of economic development but yielded culture-specific patterns, supporting the specificity principle. Both commonalities and specificities were manifested in associations between parenting and child outcomes across cultures., (© 2023 John Wiley & Sons Ltd.)

We report that unsuccessful treatment outcomes were 11.8% for tuberculosis (TB) disease and 21.8% for TB infection among persons deprived of liberty in Uganda Prisons Service facilities. Remedial efforts should include enhancing referral networks to ensure treatment continuity, strengthening data systems for complete outcome documentation, and prioritizing short-course treatment regimens.

Objective: To describe the scale-up of cervical cancer screening and treatment for women living with human immunodeficiency virus (HIV), aged 25-49 years in Uganda, and to analyse the programme data., Methods: The health ministry targeted existing HIV clinics in a 2-year scale-up of cervical cancer screening services from October 2020. In preparation, we trained health workers to assess women attending HIV clinics for screening eligibility, provided either by human papillomavirus (HPV) testing and/or visual inspection with acetic acid. Clinic staff treated women with precancerous cervical lesions with thermocoagulation or referred women with suspected cancer to external services. We analysed data reported every 6 months for the number of clinics offering screening, screening uptake, the number of positive diagnoses and the number of women who received treatment., Findings: The number of HIV clinics offering cervical cancer screening services increased from 11, before the programme launch, to 1571. During the programme, screening uptake increased from 5.0% (6506/130 293) to 107.3% (151 872/141 527) of targets. The cumulative proportion of positive diagnoses was 5.9% (23 970/407 323) overall, but was much lower for screening offering visual inspection only compared with clinics offering HPV testing. Although the proportion of women receiving treatment if positive increased from 12.8% (53/413) to 84.3% (8087/9592), the World Health Organization target of 90% was not reached., Conclusion: We demonstrated marked increases, potentially replicable by other countries, in screening and treatment. These increases could be improved further by expanding HPV testing and same-day treatment of precancerous lesions., ((c) 2024 The authors; licensee World Health Organization.)

Functionalized nanoparticles have been developed for use in nanomedicines for treating life threatening diseases including various cancers. To ensure safe use of these new nanoscale reagents, various assays for biocompatibility or cytotoxicity in vitro using cell lines often serve as preliminary assessments prior to in vivo animal testing. However, many of these assays were designed for soluble, colourless materials and may not be suitable for coloured, non-transparent nanoparticles. Moreover, cell lines are not always representative of mammalian organs in vivo. In this work, we use non-invasive impedance sensing methods with organotypic human liver HepaRG cells as a model to test the toxicity of PEG-Fe 3 O 4 magnetic nanoparticles. We also use Coherent anti-Stokes Raman Spectroscopic (CARS) microscopy to monitor the formation of lipid droplets as a parameter to the adverse effect on the HepaRG cell model. The results were also compared with two commercial testing kits (PrestoBlue and ATP) for cytotoxicity. The results suggested that the HepaRG cell model can be a more realistic model than commercial cell lines while use of impedance monitoring of Fe 3 O 4 nanoparticles circumventing the uncertainties due to colour assays. These methods can play important roles for scientists driving towards the 3Rs principle - Replacement, Reduction and Refinement., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Population-level data on durable HIV viral load suppression (VLS) following the implementation of Universal Test and Treat (UTT) in Africa are limited. We assessed trends in durable VLS and viraemia among persons living with HIV in 40 Ugandan communities during the UTT scale-up., Methods: In 2015-2020, we measured VLS (<200 RNA copies/ml) among participants in the Rakai Community Cohort Study, a longitudinal population-based HIV surveillance cohort in southern Uganda. Persons with unsuppressed viral loads were characterized as having low-level (200-999 copies/ml) or high-level (≥1000 copies/ml) viraemia. Individual virologic outcomes were assessed over two consecutive RCCS survey visits (i.e. visit-pairs; ∼18-month visit intervals) and classified as durable VLS (<200 copies/ml at both visits), new/renewed VLS (<200 copies/ml at follow-up only), viral rebound (<200 copies/ml at initial visit only) or persistent viraemia (≥200 copies/ml at both visits). Population prevalence of each outcome was assessed over calendar time. Community-level prevalence and individual-level predictors of persistent high-level viraemia were also assessed using multivariable Poisson regression with generalized estimating equations., Results: Overall, 3080 participants contributed 4604 visit-pairs over three survey rounds. Most visit-pairs (72.4%) exhibited durable VLS, with few (2.5%) experiencing viral rebound. Among those with any viraemia at the initial visit (23.5%, n = 1083), 46.9% remained viraemic through follow-up, 91.3% of which was high-level viraemia. One-fifth (20.8%) of visit-pairs exhibiting persistent high-level viraemia self-reported antiretroviral therapy (ART) use for ≥12 months. Prevalence of persistent high-level viraemia varied substantially across communities and was significantly elevated among young persons aged 15-29 years (vs. 40- to 49-year-olds; adjusted risk ratio [adjRR] = 2.96; 95% confidence interval [95% CI]: 2.21-3.96), males (vs. females; adjRR = 2.40, 95% CI: 1.87-3.07), persons reporting inconsistent condom use with non-marital/casual partners (vs. persons with marital/permanent partners only; adjRR = 1.38, 95% CI: 1.10-1.74) and persons reporting hazardous alcohol use (adjRR = 1.09, 95% CI: 1.03-1.16). The prevalence of persistent high-level viraemia was highest among males <30 years (32.0%)., Conclusions: Following universal ART provision, most persons living with HIV in south-central Uganda are durably suppressed. Among persons exhibiting any viraemia, nearly half exhibited high-level viraemia for ≥12 months and reported higher-risk behaviours associated with onward HIV transmission. Intensified efforts linking individuals to HIV treatment services could accelerate momentum towards HIV epidemic control., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Subterranean termites in the genus Reticulitermes Holmgren 1913 are among the most economically important wood-destroying pests in the western United States. Yet, there remains uncertainty regarding the taxonomy and biology of the species in this genus. The 2 species described as having distributions in this region are the western subterranean termite, Reticulitermes hesperus Banks, and the arid land subterranean termite, Reticulitermes tibialis Banks. Taxonomic studies utilizing cuticular hydrocarbon (CHC) profiles, agonistic behavior, flight phenology, and mitochondrial DNA (mtDNA) suggested that R. hesperus is a species complex comprised of 2 or more sympatric, yet reproductively isolated species. To further delineate these taxa, we examined multiple genes from samples of Reticulitermes collected in the western United States. Alates collected after recent spring and fall mating flights, as well as previously collected workers, were subjected to CHC phenotyping and DNA sequence analyses that targeted mitochondrial cytochrome oxidase subunit II (COII), mitochondrial 16S rRNA, and nuclear Internal Transcribed Spacer 1 and 2 (ITS1 and 2). Phylogenetic analyses conducted also included published sequences of other putative western Reticulitermes species. Results suggest that at least 5 species of Reticulitermes may be present in California and that Reticulitermes in Arizona consistently group into multiple clades, including samples previously identified as R. tibialis in a sister clade. These analyses further support the species status of qualitatively different CHC phenotypes and that alates swarming in spring vs. fall are reproductively isolated species., (© The Author(s) 2023. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Limited diagnostic capabilities, resources and health worker skills have deterred the advancement of birth defects surveillance systems in most low- and middle-income countries (LMICs). Empowering health workers to identify and diagnose major external birth defects (BDs) is crucial to establishing effective hospital-based BD surveillance. Makerere University-Johns Hopkins University (MU-JHU) Research Collaboration BD Surveillance System consists of three diagnostic levels: (1) surveillance midwives, (2) MU-JHU clinical team, and (3) U.S. Centers for Disease Control and Prevention (CDC) birth defects subject matter experts (SMEs) who provide confirmatory diagnosis. The diagnostic concordance of major external BDs by surveillance midwives or MU-JHU clinical team with CDC birth defects SMEs were estimated., Methods: Study staff went through a series of trainings, including birth defects identification and confirmation, before surveillance activities were implemented. To assess the diagnostic concordance, we analyzed surveillance data from 2015 to 2021 for major external BDs: anencephaly, iniencephaly, encephalocele, spina bifida, craniorachischisis, microcephaly, anophthalmia/microphthalmia, anotia/microtia, cleft palate alone, cleft lip alone, cleft lip with cleft palate, imperforate anus, hypospadias, talipes equinovarus, limb reduction, gastroschisis, and omphalocele. Positive predictive value (PPV) as the proportion of BDs diagnosed by surveillance midwives or MU-JHU clinical team that were confirmed by CDC birth defects SMEs was computed. PPVs between 2015 and 2018 and 2019-2021 were compared to assess the accuracy of case diagnosis over time., Results: Of the 204,332 infants examined during 2015-2021, 870 infants had a BD. Among the 1,245 BDs identified, 1,232 (99.0%) were confirmed by CDC birth defects SMEs. For surveillance midwives, PPV for 7 of 17 BDs was > 80%. For the MU-JHU clinical team, PPV for 13 of 17 BDs was > 80%. Among surveillance midwives, PPV improved significantly from 2015 to 2018 to 2019-2021, for microcephaly (+ 50.0%), cleft lip with cleft palate (+ 17.0%), imperforate anus (+ 30.0%), and talipes equinovarus (+ 10.8%). Improvements in PPV were also observed among MU-JHU clinical team; however, none were significant., Conclusion: The diagnostic accuracy of the midwives and clinical team increased, highlighting that BD surveillance, by front-line health care workers (midwives) in LMICs is possible when midwives receive comprehensive training, technical support, funding and continuous professional development., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Redefining viral load suppression (VLS) using lower cutpoints could impact progress towards the United Nations Programme on HIV/AIDS 95-95-95 targets. We assessed impacts of lowering the VLS cutpoint on achieving the 'third 95' in the Rakai Community Cohort Study. Population VLS would fall from 86% to 84% and 76%, respectively, after lowering VLS cutpoints from <1000 to <200 and <50 copies/ml. The fraction of viremic persons increased by 17% after lowering the VLS cutpoint from <1000 to <200 copies/ml., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This phenomenological study explored the lived experiences of survivors of childhood sexual assault, their meaning making process of the assault, and how messages from their sociocultural environment affected their relationship with, and perception of, their bodies. Utilizing a social constructivist framework, the research team interviewed eleven (n = 11) participants from a variety of backgrounds who were gender assigned female at birth and had survived childhood sexual assault (CSA). Four major themes emerged from the narratives collected. These include sociocultural impacts which included four subthemes: family relationships, peer relationships, societal and environmental influences, and cultural and ethnic influences; meaning making of the critical event, i.e., childhood sexual assault; self-perception of their bodies; internal processes that have shaped their perceptions and meaning making, i.e., thoughts, feelings, and behaviors. Findings indicate major influence of sociocultural factors in shaping participant's internal processes as survivors of CSA, meaning making, and subsequently self-perceptions of, and relationship with, their bodies. We discuss CSA and body image keeping the intersectionality of the individual, their experiences, and the impact of sociocultural contexts on that intersectionality., Competing Interests: Conflict of InterestThe authors have no conflict of interest to report., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Cyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD)., Methods: Mice with constitutive (E1 -/- ), hepatocyte-specific (Cyclin E1 Δhepa ), or intestinal-epithelial-cell-specific (Cyclin E1 ΔIEC ) inactivation of Cyclin E1 and corresponding wild type littermate controls (WT) were administered either a Lieber-DeCarli ethanol diet (LDE) for 3 weeks or acute ethanol binges (6 g/kg) through oral gavage. Serum parameters of liver functionality were measured; hepatic tissues were collected for biochemical and histological analyses., Results: The administration of acute EtOH binge and chronic LDE diet to E1 -/- mice enhanced hepatic steatosis, worsened liver damage and triggered body weight loss. Similarly, in the acute EtOH binge model, Cyclin E1 Δhepa mice revealed a significantly worsened liver phenotype. In contrast, inactivation of Cyclin E1 only in intestinal epithelial cell (IECs)did not lead to any significant changes in comparison to WT mice after acute EtOH challenge. Remarkably, both acute and chronic EtOH administration in E1 -/- animals resulted in increased levels of ADH and decreased expression of ALDH1/2. The additional application of a pan-Cdk inhibitor (S-CR8) further promoted liver damage in EtOH-treated WT mice., Conclusion: Our data point to a novel unexpected role of Cyclin E1 in hepatocytes for alcohol metabolism, which seems to be independent of the canonical Cyclin E1/Cdk2 function as a cell cycle regulator., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

During October 2016-March 2022, Uganda increased tuberculosis (TB) preventive therapy coverage among persons living with HIV from 0.6% to 88.8%. TB notification rates increased from 881.1 to 972.5 per 100,000 persons living with HIV. Timely TB screening, diagnosis, and earlier treatment should remain high priorities for TB/HIV prevention programming.

Cuticular hydrocarbon (CHC) mixtures from workers of five distinct CHC phenotypes of Reticulitermes Holmgren 1913 from two locations in northern California were examined from monthly collections taken over a 3-yr period. The objectives of this study were (1) to identify and quantify variations of the CHCs of multiple colonies of each of these phenotypes (= species or subspecies) to demonstrate consistency, (2) to assess the potential of CHC mixtures to separate or identify colonies within each phenotype, and (3) to detect any temporal changes in each of the hydrocarbons in the CHC mixtures. Nonmetric multidimensional scaling of all CHC mixtures of all samples collected at both locations separated the samples into five clearly visible, different groups of CHC phenotypes (taxa or species) of Reticulitermes. The degree of variability of the CHC mixtures among colonies of each phenotype was such that nonmetric multidimensional scaling did not separate or identify colonies. Strong seasonal fluctuations were evident in some of the CHCs of all five phenotypes and were significantly consistent with a sine curve. Maximum proportions of seasonal CHCs within a phenotype occurred in all seasons of the year but occurred mostly in the winter and summer. In general, the CHCs displaying maximum values in the winter were short-chained (C23-C27) methyl-branched alkanes, whereas the CHCs displaying maximum values in the summer were long-chained (C35-C43) methyl-branched alkanes, which likely influences water retention. These consistent chemical fingerprints are probably responsible for inter-phenotype recognition patterns and are thus useful for chemical taxonomy., (Published by Oxford University Press on behalf of Entomological Society of America 2022.)

Uganda has implemented several interventions that have contributed to prevention, early detection, and effective response to Public Health Emergencies (PHEs). However, there are gaps in collecting and documenting data on the overall response to these PHEs. We set out to establish a comprehensive electronic database of PHEs that occurred in Uganda since 2000. We constituted a core development team, developed a data dictionary, and worked with Health Information Systems Program (HISP)-Uganda to develop and customize a compendium of PHEs using the electronic Integrated Disease Surveillance and Response (eIDSR) module on the District Health Information Software version 2 (DHIS2) platform. We reviewed literature for retrospective data on PHEs for the compendium. Working with the Uganda Public Health Emergency Operations Center (PHEOC), we prospectively updated the compendium with real-time data on reported PHEs. We developed a user's guide to support future data entry teams. An operational compendium was developed within the eIDSR module of the DHIS2 platform. The variables for PHEs data collection include those that identify the type, location, nature and time to response of each PHE. The compendium has been updated with retrospective PHE data and real-time prospective data collection is ongoing. Data within this compendium is being used to generate information that can guide future outbreak response and management. The compendium development highlights the importance of documenting outbreak detection and response data in a central location for future reference. This data provides an opportunity to evaluate and inform improvements in PHEs response., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

On January 28, 2003, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the largest commitment by any nation to address a single disease in history, was announced.* In April 2004, the first person in the world to receive PEPFAR-supported antiretroviral therapy (ART) was a man aged 34 years in Uganda. Effective ART reduces morbidity and mortality among persons with HIV infection (1) and prevents both mother-to-child transmission (MTCT) (2) and sexual transmission once viral load is suppressed to undetectable levels (<200 viral copies/mL) (3). By September 2022, more than 1.3 million persons with HIV infection in Uganda were receiving PEPFAR-supported ART, an increase of approximately 5,000% from September 2004. As indicators of the ART program's effectiveness, a proxy MTCT rate decreased 77%, from 6.4% in 2010 to 1.5% in 2022, and the viral load suppression rate (<1,000 viral copies/mL) increased 3%, from 91% in 2016 to 94% in September 2022. During 2004-2022, ART scale-up helped avert nearly 500,000 HIV infections, including more than 230,000 infections among HIV-exposed infants, and approximately 600,000 HIV-related deaths. Going forward, efforts will focus on identifying all persons with HIV infection and rapidly linking them to effective ART. PEPFAR remains committed to continued strong partnership with the Government of Uganda, civil society, and other development partners toward sustainable solutions aligned with the Joint United Nations Programme on HIV/AIDS (UNAIDS) fast-track strategy to ending the global AIDS epidemic by 2030 † and safeguarding impact achieved in the long term., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: The global need for well-trained field epidemiologists has been underscored in the last decade in multiple pandemics, the most recent being COVID-19. Field Epidemiology Training Programs (FETPs) are in-service training programs that improve country capacities to respond to public health emergencies across different levels of the health system. Best practices for FETP implementation have been described previously. The Uganda Public Health Fellowship Program (PHFP), or Advanced-FETP in Uganda, is a two-year fellowship in field epidemiology funded by the U.S. Centers for Disease Control and situated in the Uganda National Institute of Public Health (UNIPH). We describe how specific attributes of the Uganda PHFP that are aligned with best practices enabled substantial contributions to the COVID-19 response in Uganda., Methods: We describe the PHFP in Uganda and review examples of how specific program characteristics facilitate integration with Ministry of Health needs and foster a strong response, using COVID-19 pandemic response activities as examples. We describe PHFP activities and outputs before and during the COVID-19 response and offer expert opinions about the impact of the program set-up on these outputs., Results: Unlike nearly all other Advanced FETPs in Africa, PHFP is delinked from an academic degree-granting program and enrolls only post-Master's-degree fellows. This enables full-time, uninterrupted commitment of academically-trained fellows to public health response. Uganda's PHFP has strong partner support in country, sufficient technical support from program staff, Ministry of Health (MoH), CDC, and partners, and full-time dedicated directorship from a well-respected MoH staff member. The PHFP is physically co-located inside the UNIPH with the emergency operations center (EOC), which provides a direct path for health alerts to be investigated by fellows. It has recognized value within the MoH, which integrates graduates into key MoH and partner positions. During February 2020-September 2021, PHFP fellows and graduates completed 67 major COVID-related projects. PHFP activities during the COVID-19 response were specifically requested by the MoH or by partners, or generated de novo by the program, and were supervised by all partners., Conclusion: Specific attributes of the PHFP enable effective service to the Ministry of Health in Uganda. Among the most important is the enrollment of post-graduate fellows, which leads to a high level of utilization of the program fellows by the Ministry of Health to fulfill real-time needs. Strong leadership and sufficient technical support permitted meaningful program outputs during COVID-19 pandemic response. Ensuring the inclusion of similar characteristics when implementing FETPs elsewhere may allow them to achieve a high level of impact., (© 2022. The Author(s).)

Introduction: The potential disruption in antiretroviral therapy (ART) services in Africa at the start of the COVID-19 pandemic raised concern for increased morbidity and mortality among people living with HIV (PLHIV). We describe HIV treatment trends before and during the pandemic and interventions implemented to mitigate COVID-19 impact among countries supported by the US Centers for Disease Control and Prevention (CDC) through the President's Emergency Plan for AIDS Relief (PEPFAR)., Methods: We analysed quantitative and qualitative data reported by 10,387 PEPFAR-CDC-supported ART sites in 19 African countries between October 2019 and March 2021. Trends in PLHIV on ART, new ART initiations and treatment interruptions were assessed. Viral load coverage (testing of eligible PLHIV) and viral suppression were calculated at select time points. Qualitative data were analysed to summarize facility- and community-based interventions implemented to mitigate COVID-19., Results: The total number of PLHIV on ART increased quarterly from October 2019 (n = 7,540,592) to March 2021 (n = 8,513,572). The adult population (≥15 years) on ART increased by 14.0% (7,005,959-7,983,793), while the paediatric population (<15 years) on ART declined by 2.6% (333,178-324,441). However, the number of new ART initiations dropped between March 2020 and June 2020 by 23.4% for adults and 26.1% for children, with more rapid recovery in adults than children from September 2020 onwards. Viral load coverage increased slightly from April 2020 to March 2021 (75-78%) and viral load suppression increased from October 2019 to March 2021 (91-94%) among adults and children combined. The most reported interventions included multi-month dispensing (MMD) of ART, community service delivery expansion, and technology and virtual platforms use for client engagement and site-level monitoring. MMD of ≥3 months increased from 52% in October 2019 to 78% of PLHIV ≥ age 15 on ART in March 2021., Conclusions: With an overall increase in the number of people on ART, HIV programmes proved to be resilient, mitigating the impact of COVID-19. However, the decline in the number of children on ART warrants urgent investigation and interventions to prevent further losses experienced during the COVID-19 pandemic and future public health emergencies., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Uganda is highly vulnerable to public health emergencies (PHEs) due to its geographic location next to the Congo Basin epidemic hot spot, placement within multiple epidemic belts, high population growth rates, and refugee influx. In view of this, Uganda's Ministry of Health established the Public Health Emergency Operations Center (PHEOC) in September 2013, as a central coordination unit for all PHEs in the country. Uganda followed the World Health Organization's framework to establish the PHEOC, including establishing a steering committee, acquiring legal authority, developing emergency response plans, and developing a concept of operations. The same framework governs the PHEOC's daily activities. Between January 2014 and December 2021, Uganda's PHEOC coordinated response to 271 PHEs, hosted 207 emergency coordination meetings, trained all core staff in public health emergency management principles, participated in 21 simulation exercises, coordinated Uganda's Global Health Security Agenda activities, established 6 subnational PHEOCs, and strengthened the capacity of 7 countries in public health emergency management. In this article, we discuss the following lessons learned: PHEOCs are key in PHE coordination and thus mitigate the associated adverse impacts; although the functions of a PHEOC may be legalized by the existence of a National Institute of Public Health, their establishment may precede formally securing the legal framework; staff may learn public health emergency management principles on the job; involvement of leaders and health partners is crucial to the success of a public health emergency management program; subnational PHEOCs are resourceful in mounting regional responses to PHEs; and service on the PHE Strategic Committee may be voluntary.

Uganda is an ecological hot spot with porous borders that lies in several infectious disease transmission belts, making it prone to disease outbreaks. To prepare and respond to these public health threats and emergencies in a coordinated manner, Uganda established the Uganda National Institute of Public Health (UNIPH) in 2013.Using a step-by-step process, Uganda's Ministry of Health (MOH) crafted a strategy with a vision, mission, goal, and strategic objectives, and identified value additions and key enablers for success. A regulatory impact assessment was then conducted to inform the drafting of principles of the bill for legislation on the Institute.Despite not yet attaining legal status, the UNIPH has already achieved faster, smarter, and more efficient and effective prevention, detection, and response to public health emergencies. Successes include a more coordinated multisectoral, disciplined, and organized response to emergencies; appropriate, timely, and complete information receipt and sharing; a functional national lab sample and results transportation network that has enabled detection and confirmation of public health events within 48 hours of alert; appropriate response to a confirmed public health event in 24-48 hours; and real-time surveillance of endemic- and epidemic-prone diseases.In this article, we document success stories, lessons learned, and challenges encountered during the unique staged process used to develop the components of the UNIPH. The creation of an integrated disease control center has proven to yield better collaboration and synergies between different arms of epidemic preparedness and response., (© Ario et al.)

Metacognition is theorized to play a central role in children's mathematics learning. The primary goal of the current study was to provide experimental evidence in support of this role with elementary school students learning about mathematical equivalence. The final sample included 135 children (59 first-graders and 76 second-graders) who participated in the study across three sessions in their classrooms. They completed a pretest during session one, a lesson and posttest during session two, and a two-week delayed retention test during session three. For session two, children were randomly assigned to receive a lesson on mathematical equivalence with or without integrated metacognitive questions. Relative to the control lesson, children who received the metacognitive lesson demonstrated higher accuracy and higher metacognitive monitoring scores on the posttest and retention test. Further, these benefits sometimes extended to uninstructed items targeting arithmetic and place value. No condition effects were observed for children's metacognitive control skills within any of the topics. These findings suggest a brief metacognitive lesson can improve children's mathematics understanding.

Objectives: Personality researchers have found that dispositional traits are typically stabile over the life course, but shyness is one trait that has rarely been examined in later life. Shyness as a global trait has been linked negatively to multiple psychological indices of childhood well-being, including loneliness. Despite the fact that older adults may already be at risk for experiencing heightened loneliness, regret, or decreased fulfillment, research has not assessed these experiences in relation to personality in later life. In the past few decades, research on social withdrawal has moved beyond treating shyness as a global trait and started to examine the multiple motivations behind socially withdrawn behavior. Method: Employing data from 309 older participants of the Huntsman Senior Games, the current study used regression analyses to examine the potential relations between three forms of withdrawal (shyness, avoidance, and unsociability) and loneliness, regret, and fulfillment in later life. Results and Conclusion: Results indicated that shyness, avoidance, and unsociability, respectively, were significantly associated with increased loneliness and regret, and decreased fulfillment. Further, marital status (married, divorced, widowed) moderated links between withdrawal and psychological indices of well-being in later life.

Objective: Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA)., Design: A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay., Results: An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut., Conclusion: Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.

Background: Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA., Methods: Cholangiocarcinogenesis was induced in rats (TAA) and mice (Jnk Δhepa  + CCl 4  + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRAS G12D cells. Cell signaling, growth, gene regulation and [U- 13 C]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model., Results: Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRAS G12D can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRAS G12D promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRAS G12D CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression., Conclusions: In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA., (© 2022. The Author(s).)

Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro , Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo , Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105 + cancer stem cells (CSCs) and CD105 - non-CSCs in vivo . Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau ( VHL ) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC.

Despite remarkable progress in controlling HIV and TB, Uganda is one of the 30 high-burden TB/HIV countries. Approximately 53,000 Ugandans had a new HIV diagnosis in 2019, and approximately 88,000 Ugandans had a TB diagnosis in 2020. Fellows in the Uganda Public Health Fellowship Program (UPHFP) work directly with the Ministry of Health AIDS and TB Control Programs, the U.S. Centers for Disease Control and Prevention, UPHFP supervisors, and implementing partners to investigate and evaluate HIV-related and TB-related issues. These activities have contributed to the Uganda HIV and TB programs. UPHFP fellows complete projects in 7 competency domains, including outbreak investigations, surveillance evaluations, and data quality improvement. Priority HIV/AIDS/TB information gaps/topics are identified in consultation with key stakeholders, and fellows complete projects to guide program improvements and policy decisions. During 2015-2020, UPHFP fellows implemented 127 HIV and TB projects covering key program areas in AIDS and TB control programs, including care and treatment (16 projects), TB/HIV (18), prevention of mother-to-child HIV transmission (24), key and priority populations (9), pre-exposure and post-exposure prophylaxis (7), adolescent girls and young women (6), service delivery (13), and diagnosis of TB including drug-resistant TB and TB in high-risk groups (32). These projects have helped improve retention, quality of care, and treatment outcomes for people living with HIV, HIV and TB coinfected patients, and TB patients. They have also contributed to the decrease in pediatric TB and infant HIV positivity rates and improved service delivery for key populations. UPHFP results were disseminated to relevant stakeholders such as government departments, implementing partners, districts, and the general community and guided decision making. UPHFP has significantly improved HIV and TB control in Uganda. Other countries with similar programs could benefit from this approach and utilize program fellows to support HIV and TB control., (© Ario et al.)

Children often struggle to solve mathematical equivalence problems correctly. The change-resistance theory offers an explanation for children's difficulties and suggests that some incorrect strategies represent the overgeneralization of children's narrow arithmetic experience. The current research considered children's metacognitive abilities to test a tacit assumption of the change-resistance theory by providing a novel empirical examination of children's strategy use and certainty ratings. Children were recruited from U.S. elementary school classrooms serving predominantly White students between the ages of 6 and 9. In Study 1 ( n = 52) and Study 2 ( n = 147), children were more certain that they were correct when they employed arithmetic-specific incorrect strategies relative to other incorrect strategies. These findings are consistent with the change-resistance theory and have implications for the development of children's metacognition., Competing Interests: Declaration of interest: None

Acetaminophen (APAP) hepatotoxicity induces endoplasmic reticulum (ER) stress which triggers the unfolded protein response (UPR) in hepatocytes. However, the mechanisms underlying ER stress remain poorly understood, thus reducing the options for exploring new pharmacological therapies for patients with hyperacute liver injury. Eight-to-twelve-week-old C57BL/6J Xbp1-floxed (Xbp1 f/f ) and hepatocyte-specific knockout Xbp1 mice (Xbp1 ∆hepa ) were challenged with either high dose APAP [500 mg/kg] and sacrificed at early (1-2 h) and late (24 h) stages of hepatotoxicity. Histopathological examination of livers, immunofluorescence and immunohistochemistry, Western blot, real time (RT)-qPCR studies and transmission electron microscopy (TEM) were performed. Pharmacological inhibition of XBP1 using pre-treatment with STF-083010 [STF, 75 mg/kg] and autophagy induction with Rapamycin [RAPA, 8 mg/kg] or blockade with Chloroquine [CQ, 60 mg/kg] was also undertaken in vivo. Cytoplasmic expression of XBP1 coincided with severity of human and murine hyperacute liver injury. Transcriptional and translational activation of the UPR and sustained activation of JNK1/2 were major events in APAP hepatotoxicity, both in a human hepatocytic cell line and in a preclinical model. Xbp1 ∆hepa livers showed decreased UPR and JNK1/2 activation but enhanced autophagy in response to high dose APAP. Additionally, blockade of XBP1 splicing by STF, mitigated APAP-induced liver injury and without non-specific off-target effects (e.g., CYP2E1 activity). Furthermore, enhanced autophagy might be responsible for modulating CYP2E1 activity in Xbp1 ∆hepa animals. Genetic and pharmacological inhibition of Xbp1 specifically in hepatocytes ameliorated APAP-induced liver injury by enhancing autophagy and decreasing CYP2E1 expression. These findings provide the basis for the therapeutic restoration of ER stress and/or induction of autophagy in patients with hyperacute liver injury., (© 2022. The Author(s).)

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 ( Jnk1/2 ) knockout mice. Floxed JNK1/2 ( Jnk f/f ) and Jnk ∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines ( Tnf , Tgfβ1 ) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk ∆hepa compared with Jnk f/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk ∆hepa animals compared with Jnk f/f littermates. Finally, thioacetamide (TAA) administration to Jnk ∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl 4 -treated Jnk ∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.