Effectiveness of ChAdOx1 nCoV-19 and BBIBP-CorV vaccines against COVID-19-associated hospitalisation and death in the Seychelles infected adult population.

BACKGROUND: The Seychelles COVID-19 vaccination campaign was initiated using two different vaccines during the first wave of the pandemic in 2021. This observational study estimated vaccine effectiveness against severe outcomes (hospitalisation and/or death) from individuals infected with COVID-19 in the Seychelles adult population during Beta and Delta variant transmission. METHODS: This nationwide retrospective cohort study included all Seychellois residents aged ≥ 18 years who tested positive by RT-PCR or rapid antigen test for COVID-19 between January 25, 2021, and June 30, 2021. We measured the relative risk (RR) of laboratory-confirmed SARS-CoV-2 hospitalisation and/or death among individuals partially or fully vaccinated with ChAdOx1 nCoV-19 (SII Covishield) or BBIBP-CorV (Sinopharm) vaccines compared to unvaccinated individuals using modified Poisson regression. Controlling for age, gender and calendar month, vaccine effectiveness was estimated as 1-RR ≥14 days after the first dose and ≥7 days after the second dose for each available vaccine versus an unvaccinated control group. RESULTS: A total of 12,326 COVID-19 infections were reported in adult Seychellois residents between January 25, 2021, and June 30, 2021. Of these, 1,287 individuals received one dose of either BBIBP-CorV (Sinopharm) or ChAdOx1-nCoV-19 (SII Covishield) vaccine, and 5,225 individuals received two doses. Estimated adjusted effectiveness of two doses of either Sinopharm or SII Covishield was high, at 70% (95% CI 58%-78%) and 71% (95% CI 62%-78%) respectively. Sinopharm maintained high levels of protection against severe outcomes in partially vaccinated individuals at 61% (95% CI 36%-76%), while the effectiveness of one dose of SII Covishield was low at 29% (95% CI 1%-49%). CONCLUSIONS: This observational study demonstrated high levels of protection of two doses of two vaccine types against severe outcomes of COVID-19 during the first wave of the pandemic driven by Beta (B.1.351) and Delta (B.1.617.2) variant predominance. One dose of ChAdOx1-nCoV-19 (Covishield SII) was found to be inadequate in protecting the general adult population against hospitalisation and/or death from COVID-19.

Fish consumption and its lipid modifying effects - A review of intervention studies.

Fish is an important source of nutrients, particularly the long chain n-3 polyunsaturated fatty acids (n-3 PUFAs). The incorporation of fish into the diet has been shown to have several health benefits, including lowering the risk of cardiovascular disease (CVD). Elevated plasma lipids are one of the main modifiable risk factors contributing to CVD and may be partly mediated by n-3 PUFAs. Although n-3 PUFAs in the form of supplementation have been shown to exert lipid modifying effects, the effects of fish consumption on the lipid profile have not been well summarised to date. Therefore, the aim of the present review is to discuss the current evidence from intervention studies investigating the effect of fish consumption on the lipid profile in both apparently healthy and non-healthy populations. Existing evidence appears to support the role of fish in promoting a shift towards a less inflammatory lipid profile through raising n-3 PUFAs and potentially lowering n-6 PUFA and triglyceride concentrations in both healthy and non-healthy populations. Fish consumption has a negligible effect on cholesterol concentrations; however, fish consumption may promote a small increase in high density lipoprotein (HDL) cholesterol amongst people with lower HDL at baseline. Limited studies have shown fish consumption to result in shifts in phospholipid and sphingolipid species and structure, albeit it is not yet clear whether these alterations have any meaningful impact on CVD risk. Future well-designed studies that utilise NMR and/or lipidomics analysis are warranted to explore the effects of these shifts in lipid content and structure in the context of disease development. Public health guidance should emphasise the cardioprotective benefits of fish and encourage consumption particularly in the Global North where fish consumption remains low.

Our evolved understanding of the human health risks of mercury.

Mercury (Hg) is a chemical of health concern worldwide that is now being acted upon through the Minamata Convention. Operationalizing the Convention and tracking its effectiveness requires empathy of the diversity and variation of mercury exposure and risk in populations worldwide. As part of the health plenary for the 15th International Conference on Mercury as a Global Pollutant (ICMGP), this review paper details how scientific understandings have evolved over time, from tragic poisoning events in the mid-twentieth century to important epidemiological studies in the late-twentieth century in the Seychelles and Faroe Islands, the Arctic and Amazon. Entering the twenty-first century, studies on diverse source-exposure scenarios (e.g., ASGM, amalgams, contaminated sites, cosmetics, electronic waste) from across global regions have expanded understandings and exemplified the need to consider socio-environmental variables and local contexts when conducting health studies. We conclude with perspectives on next steps for mercury health research in the post-Minamata Convention era.

Who Needs Big Health Sector Reforms Anyway? Seychelles' Road to UHC Provides Lessons for Sub-Saharan Africa and Island Nations.

The road to universal health coverage (UHC) needs not be driven by big reforms that include the initiation of health insurance, provider-funder separation, results-based financing, or other large health sector reforms advocated in many countries in sub-Saharan Africa and elsewhere. The Seychelles experience, documented through a series of analytical products like public expenditure reviews and supporting surveys with assistance from the World Bank and World Health Organization (WHO), shows an alternative, more incremental reform road to UHC, with important lessons to the region and other small-population or island nations. Done well, in some countries, a basic supply-side funded, publicly owned and operated, and integrated health system can produce excellent health outcomes in a cost-effective and sustainable way. The article traces some of the factors that facilitated this success in the Seychelles, including high political commitment, strong voice and a downward accountability culture, strong public health functions, and an impressive investment in primary health care. These factors help explain past successes and also provide a good basis for adaptation of health systems to dramatic shifts in the epidemiological and demographic transitions, disease outbreaks, and rising public expectation and demand for high quality of care. Once again, how the Seychelles responds can show the way for other countries in the region and elsewhere regardless of the types of reforms countries engage in.

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism.

The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.

Characterization of MYC-induced tumorigenesis by in situ lipid profiling.

We apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to provide an in situ lipidomic profile of genetically modified tissues from a conditional transgenic mouse model of MYC-induced hepatocellular carcinoma (HCC). This unique, label-free approach of combining DESI-MSI with the ability to turn specific genes on and off has led to the discovery of highly specific lipid molecules associated with MYC-induced tumor onset. We are able to distinguish normal from MYC-induced malignant cells. Our approach provides a strategy to define a precise molecular picture at a resolution of about 200 µm that may be useful in identifying lipid molecules that define how the MYC oncogene initiates and maintains tumorigenesis.

Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

High throughput automated chromatin immunoprecipitation as a platform for drug screening and antibody validation.

Chromatin immunoprecipitation (ChIP) is an assay for interrogating protein-DNA interactions that is increasingly being used for drug target discovery and screening applications. Currently the complexity of the protocol and the amount of hands-on time required for this assay limits its use to low throughput applications; furthermore, variability in antibody quality poses an additional obstacle in scaling up ChIP for large scale screening purposes. To address these challenges, we report HTChIP, an automated microfluidic-based platform for performing high-throughput ChIP screening measurements of 16 different targets simultaneously, with potential for further scale-up. From chromatin to analyzable PCR results only takes one day using HTChIP, as compared to several days up to one week for conventional protocols. HTChIP can also be used to test multiple antibodies and select the best performer for downstream ChIP applications, saving time and reagent costs of unsuccessful ChIP assays as a result of poor antibody quality. We performed a series of characterization assays to demonstrate that HTChIP can rapidly and accurately evaluate the epigenetic states of a cell, and that it is sensitive enough to detect the changes in the epigenetic state induced by a cytokine stimulant over a fine temporal resolution. With these results, we believe that HTChIP can introduce large improvements in routine ChIP, antibody screening, and drug screening efficiency, and further facilitate the use of ChIP as a valuable tool for research and discovery.

Nitric oxide induces cell death by regulating anti-apoptotic BCL-2 family members.

Nitric oxide (NO) activates the intrinsic apoptotic pathway to induce cell death. However, the mechanism by which this pathway is activated in cells exposed to NO is not known. Here we report that BAX and BAK are activated by NO and that cytochrome c is released from the mitochondria. Cells deficient in Bax and Bak or Caspase-9 are completely protected from NO-induced cell death. The individual loss of the BH3-only proteins, Bim, Bid, Puma, Bad or Noxa, or Bid knockdown in Bim(-/-)/Puma(-/-) MEFs, does not prevent NO-induced cell death. Our data show that the anti-apoptotic protein MCL-1 undergoes ASK1-JNK1 mediated degradation upon exposure to NO, and that cells deficient in either Ask1 or Jnk1 are protected against NO-induced cell death. NO can inhibit the mitochondrial electron transport chain resulting in an increase in superoxide generation and peroxynitrite formation. However, scavengers of ROS or peroxynitrite do not prevent NO-induced cell death. Collectively, these data indicate that NO degrades MCL-1 through the ASK1-JNK1 axis to induce BAX/BAK-dependent cell death.

BH3 peptides induce mitochondrial fission and cell death independent of BAX/BAK.

BH3 only proteins trigger cell death by interacting with pro- and anti-apoptotic members of the BCL-2 family of proteins. Here we report that BH3 peptides corresponding to the death domain of BH3-only proteins, which bind all the pro-survival BCL-2 family proteins, induce cell death in the absence of BAX and BAK. The BH3 peptides did not cause the release of cytochrome c from isolated mitochondria or from mitochondria in cells. However, the BH3 peptides did cause a decrease in mitochondrial membrane potential but did not induce the opening of the mitochondrial permeability transition pore. Interestingly, the BH3 peptides induced mitochondria to undergo fission in the absence of BAX and BAK. The binding of BCL-X(L) with dynamin-related protein 1 (DRP1), a GTPase known to regulate mitochondrial fission, increased in the presence of BH3 peptides. These results suggest that pro-survival BCL-2 proteins regulate mitochondrial fission and cell death in the absence of BAX and BAK.

Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS.

Senescence is a potential tumor-suppressing mechanism and a commonly used model of cellular aging. One current hypothesis to explain senescence, based in part on the correlation of oxygen with senescence, postulates that it is caused by oxidative damage from reactive oxygen species (ROS). Here, we further test this theory by determining the mechanisms of hyperoxia-induced senescence. Exposure to 70% O(2) led to stress-induced, telomere-independent senescence. Although hyperoxia elevated mitochondrial ROS production, overexpression of antioxidant proteins was not sufficient to prevent hyperoxia-induced senescence. Hyperoxia activated AMPK; however, overexpression of a kinase-dead mutant of LKB1, which prevented AMPK activation, did not prevent hyperoxia-induced senescence. Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence. However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53. Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence. Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia.

Bcl-2 family members regulate anoxia-induced cell death.

The mechanisms underlying anoxia (0-0.5% oxygen)-induced cell death are not fully understood. Here we discuss the mechanisms by which cells undergo apoptosis in the absence of oxygen. Cell death during anoxia occurs via the intrinsic pathway of apoptosis. Key regulators of apoptosis during anoxia are the Bcl-2 family of proteins. The pathway is initiated by the loss of function of the prosurvival Bcl-2 family members Mcl-1 and Bcl-2/Bcl-XL, resulting in Bax- or Bak-dependent release of cytochrome c and subsequent caspase-9-dependent cell death.

Role of Bcl-2 family members in anoxia induced cell death.

Anoxia, the condition of oxygen deprivation, induces apoptosis via the intrinsic apoptotic pathway. Cells deficient in both Bax and Bak do not undergo cell death during anoxia. However, the underlying mechanism of anoxia induced cell death is not well defined. Here we report our latest findings of two critical events that are required to induce cell death during anoxia. First, a key member of the Bcl-2 family of pro-survival proteins, Mcl-1, undergoes proteasomal-dependent degradation. The loss of Mcl-1 protein is independent of Bax or Bak indicating this is an early event in the apoptotic cascade. Second, cells inhibit the mitochondrial electron transport chain to negate the pro-survival function of Bcl-2/Bcl-X(L). These observations indicate that loss of pro-survival function is necessary for anoxia induced cell death.

Loss of Mcl-1 protein and inhibition of electron transport chain together induce anoxic cell death.

How cells die in the absence of oxygen (anoxia) is not understood. Here we report that cells deficient in Bax and Bak or caspase-9 do not undergo anoxia-induced cell death. However, the caspase-9 null cells do not survive reoxygenation due to the generation of mitochondrial reactive oxygen species. The individual loss of Bim, Bid, Puma, Noxa, Bad, caspase-2, or hypoxia-inducible factor 1beta, which are potential upstream regulators of Bax or Bak, did not prevent anoxia-induced cell death. Anoxia triggered the loss of the Mcl-1 protein upstream of Bax/Bak activation. Cells containing a mitochondrial DNA cytochrome b 4-base-pair deletion ([rho(-)] cells) and cells depleted of their entire mitochondrial DNA ([rho(0)] cells) are oxidative phosphorylation incompetent and displayed loss of the Mcl-1 protein under anoxia. [rho(0)] cells, in contrast to [rho(-)] cells, did not die under anoxia. However, [rho(0)] cells did undergo cell death in the presence of the Bad BH3 peptide, an inhibitor of Bcl-X(L)/Bcl-2 proteins. These results indicate that [rho(0)] cells survive under anoxia despite the loss of Mcl-1 protein due to residual prosurvival activity of the Bcl-X(L)/Bcl-2 proteins. Collectively, these results demonstrate that anoxia-induced cell death requires the loss of Mcl-1 protein and inhibition of the electron transport chain to negate Bcl-X(L)/Bcl-2 proteins.

Two functional epitopes of pigment epithelial-derived factor block angiogenesis and induce differentiation in prostate cancer.

Pigment epithelial-derived factor (PEDF), an angiogenesis inhibitor with neurotrophic properties, balances angiogenesis in the eye and blocks tumor progression. Its neurotrophic function and the ability to block vascular leakage is replicated by the PEDF 44-mer peptide (residues 58-101). We analyzed PEDFs' three-dimensional structure and identified a potential receptor-binding surface. Seeking PEDF-based antiangiogenic agents we generated and tested peptides representing the middle and lower regions of this surface. We identified previously unknown antiangiogenic epitopes consisting of the 34-mer (residues 24-57) and a shorter proximal peptide (TGA, residues 16-26) with the critical stretch L19VEEED24 and a fragment within the 44-mer (ERT, residues 78-94), which retained neurotrophic activity. The 34-mer and TGA, but not the 44-mer reproduced PEDF angioinhibitory signals hinged on c-jun-NH2-kinase-dependent nuclear factor of activated T cell deactivation and caused apoptosis. Conversely, the ERT, but not the 34-mer/TGA induced neuronal differentiation. For the 44-mer/ERT, we showed a novel ability to cause neuroendocrine differentiation in prostate cancer cells. PEDF and the peptides bound endothelial and PC-3 prostate cancer cells. Bound peptides were displaced by PEDF, but not by each other, suggesting multiple receptors. PEDF and its active fragments blocked tumor formation when conditionally expressed by PC-3 cells. The 34- and 44-mer used distinct mechanisms: the 34-mer acted on endothelial cells, blocked angiogenesis, and induced apoptosis whereas 44-mer prompted neuroendocrine differentiation in cancer cells. Our results map active regions for the two PEDF functions, signaling via distinct receptors, identify candidate peptides, and provide their mechanism of action for future development of PEDF-based tumor therapies.

Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510.

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), 15-deoxy-delta(12,14)-prostaglandin J2, troglitazone, and rosiglitazone increased PPARgamma and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARgamma ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARgamma ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Nuclear factor of activated T cells balances angiogenesis activation and inhibition.

It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial-derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain-like interleukin 1beta-converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.