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Abstract Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with “epidrugs” is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Our findings demonstrate that targeting polycomb demethylases is a new potent pharmacologic strategy for treating cisplatin resistant TGCTs that warrants clinical development.

G0/G1 switch gene 2 (G0S2) is known to inhibit lipolysis by inhibiting adipose triglyceride lipase (ATGL). In this report, we dissect the role of G0S2 in ER+ versus ER- breast cancer. Overexpression of G0S2 in ER- cells increased cell proliferation, while G0S2 overexpression in ER+ cells decreased cell proliferation. Transcriptome analysis revealed that G0S2 mediated distinct but overlapping transcriptional responses in ER- and ER+ cells. G0S2 reduced genes associated with an epithelial phenotype, especially in ER- cells, including CDH1, ELF3, STEAP4 and TACSTD2, suggesting promotion of the epithelial-mesenchymal transition (EMT). G0S2 also repressed estrogen signaling and estrogen receptor target gene signatures, especially in ER+ cells, including TFF1 and TFF3. In addition, G0S2 overexpression increased cell migration in ER- cells and increased estrogen deprivation sensitivity in ER+ cells. Interestingly, two genes downstream of ATGL in fat utilization and very important in steroid hormone biosynthesis, HMGCS1 and HMGCS2, were downregulated in G0S2 overexpressing ER+ cells. In addition, HSD17B11, a gene that converts estradiol to its less estrogenic derivative, estrone, was highly upregulated in G0S2 overexpressing ER+ cells, suggesting G0S2 overexpression has a negative effect on estradiol production and maintenance. High expression of G0S2 and HSD17B11 was associated with improved relapse-free survival in breast cancer patients while high expression of HMGSC1 was associated with poor survival. Finally, we deleted G0S2 in breast cancer-prone MMTV-PyMT mice. Our data indicates a complex role for G0S2 in breast cancer, dependent on ER status, that may be partially mediated by suppression of the estrogen signaling pathway.

The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recently emergent human and environmental health concern. There is a consistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, no mechanistic studies have been performed to date concerning PFAS and TGCTs. In this report, the effects of the legacy PFAS perfluorooctanesulfonic acid (PFOS) and the newer “clean energy” PFAS lithium bis(trifluoromethylsulfonyl)imide (LiTFSi, called HQ-115), on the tumorigenicity of TGCTs in mice, TGCT cell survival, and metabolite production, as well as gene regulation were investigated. In vitro, the proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide range of PFOS and HQ-115 concentrations. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistent with human exposure but induced minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression alterations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways that were previously showed to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar patterns of PFOS-mediated gene expression occurred in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acid-based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, is the first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recently emergent human and environmental health concern. There is a consistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, no mechanistic studies have been performed to date concerning PFAS and TGCTs. In this report, the effects of the legacy PFAS perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS lithium bis(trifluoromethylsulfonyl)imide (LiTFSi, called HQ-115), on the tumorigenicity of TGCTs in mice, TGCT cell survival, and metabolite production, as well as gene regulation were investigated. In vitro, the proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide range of PFOS and HQ-115 concentrations. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistent with human exposure but induced minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression alterations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways that were previously showed to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar patterns of PFOS-mediated gene expression occurred in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acid-based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, is the first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class. [ABSTRACT FROM AUTHOR]

Background: Aortic stiffening is a well-known cardiovascular risk factor. Computed tomography (CT) has proven to be a valuable tool in the assessment of aortic elastic properties. Drugs that inhibit the renin-angiotensin system (RAS) play a central role in cardioprotective therapy. We aimed to evaluate the relationship between aortic elastic properties and RAS-targeted therapy in hypertensive patients. Methods: This is an observational prospective study of hypertensive patients with nonobstructive coronary artery disease who underwent coronary CT angiography (CCTA). Aortic compliance and distensibility were calculated from the ECG-gated CCTA image. Patients were divided into two groups − those with RAS-targeted therapy − RAS(+) and those with non-RAS-targeted therapy − RAS(−). The elastic properties of the aorta were compared between the two groups. Results: A total of 142 patients were included in the final analysis. 53.5 % of the population were in the RAS(+) group and 46.5 % in the RAS(−) group. Elastic properties of ascending and descending aorta were significantly higher in the RAS(+) group compared to the RAS(−) group: AA compliance 1.42 ± 0.75 mm2/mmHg in the RAS(+) vs 1.03 ± 0.91 mm2/mmHg in the RAS(−), p = 0.024; AA distensibility 2.86 ± 1.11 x10-3mm3 in the RAS(+) vs 1.82 ± 0.97 x10-3mm3 in RAS(−), p

Abstract Electrochemical CO2 reduction reaction in aqueous electrolytes is a promising route to produce added-value chemicals and decrease carbon emissions. However, even in Gas-Diffusion Electrode devices, low aqueous CO2 solubility limits catalysis rate and selectivity. Here, we demonstrate that when assembled over a heterogeneous electrocatalyst, a film of nitrile-modified Metal-Organic Framework (MOF) acts as a remarkable CO2-solvation layer that increases its local concentration by ~27-fold compared to bulk electrolyte, reaching 0.82 M. When mounted on a Bi catalyst in a Gas Diffusion Electrode, the MOF drastically improves CO2-to-HCOOH conversion, reaching above 90% selectivity and partial HCOOH currents of 166 mA/cm2 (at −0.9 V vs RHE). The MOF also facilitates catalysis through stabilization of reaction intermediates, as identified by operando infrared spectroscopy and Density Functional Theory. Hence, the presented strategy provides new molecular means to enhance heterogeneous electrochemical CO2 reduction reaction, leading it closer to the requirements for practical implementation.

Abstract Background The commercial sector plays a vital role in mosquito net ownership and access in Tanzania. The National Malaria Strategic Plan (NMSP) includes long-lasting insecticidal nets (LLIN) delivery through the commercial sector as a complementary mechanism. The NMSP aims to increase LLIN sales while decreasing untreated mosquito net sales. This survey aimed to track quantities, market share of different net categories, prices, and origins of mosquito nets in retail markets and to engage stakeholders to analyse market trends. Methods This mixed-method mosquito net retail outlet survey was conducted in mid-2021 in six and in mid-2022 in eight regions. Field teams identified net-selling outlets in major urban and peri-urban markets and used snowball sampling to identify additional outlets. A structured questionnaire was used, and photos of available mosquito net products were taken. Key informant interviews were conducted with wholesalers and retailers. The relative market share of a product was calculated by using the mean of each sales category as frequency weights. Qualitative data analysis was undertaken by summarizing common themes and observations based on the research question. Results A total of 394 and 1139 outlets were surveyed in 2021 and 2022, respectively. More than 96% of distributed brands in both years were untreated nets. The market share for untreated mosquito nets was 99.2% in 2021 and 88.3% in 2022. Bed net sales were seasonal, peaking in the rainy season and at the start of the school year. Leaked LLINs from the public sector comprised 0.3% of the market share in 2021 and 8.3% in 2022. Kigoma markets had the most significant frequency of leaked LLIN products. Legitimate LLINs were rare in 2021 (n = 2) and not found in 2022, despite the presence of a local LLIN manufacturer. A small number (n = 3) of untreated nets fabricated in China claiming to be LLINs were observed in 2022. Conclusions Despite NMCP’s strategic approach to increasing retail market share for legitimate LLINs, significant challenges remain. Efforts are needed to change the current situation given the context of large-scale public sector distributions of LLINs, the higher consumer cost of LLINs, the lack of bed net varieties. Improvement of registration process is recommended.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs. [ABSTRACT FROM AUTHOR]

Abstract Metal‐Organic Frameworks (MOFs) hold great potential to be used as porous (photo)‐electrocatalytic platforms containing large concentration of immobilized molecular catalysts. Indeed, the use of MOFs in a photo‐electrochemical devices was recently demonstrated. However, so far there are no reports of MOFs used for photo‐electrochemical O2 reduction to H2O2. Herein, we utilize a Co‐porphyrin based MOF (Co‐MOF‐525), that produces H2O2 at high faradaic efficiency (95 %), both electrochemically and photo‐electrochemically. Electrochemical characterization show that the active catalytic site is a MOF‐tethered Co(I)‐porphyrin. Additionally, under light illumination, the MOF's intrinsic catalytic rate is significantly accelerated compared to dark electrolysis conditions. Thus, this work could open a path for future implementation of photoactive MOFs in solar fuel schemes.

Abstract Background Since 2013, the National Malaria Control Programme in mainland Tanzania and the Zanzibar Malaria Elimination Programme have implemented mass insecticide-treated net (ITN) distribution campaigns, routine ITN distribution to pregnant women and infants, and continuous distribution through primary schools (mainland) and community leaders (Zanzibar) to further malaria control efforts. Mass campaigns are triggered when ITN access falls below 40%. In this context, there is a need to monitor ITN access annually to assess whether it is below threshold and inform quantification of ITNs for the following year. Annual estimates of access are needed at the council level to inform programmatic decision-making. Methods An age-structured stock and flow model was used to predict annual net crops from council-level distribution data in Tanzania from 2012 to 2020 parameterized with a Tanzania-specific net median lifespan of 2.15 years. Annual nets-per-capita (NPC) was calculated by dividing each annual net crop by mid-year council projected population. A previously fit nonparametric conditional quantile function for the proportion of the population with access to an ITN (ITN access) as a function of NPC was used to predict ITN access at the council level based on the predicted NPC value. These estimates were compared to regional-level ITN access from large household surveys. Results For regions with the same ITN strategy for all councils, predicted council-level ITN access was consistent with regional-level survey data for 79% of councils. Regions where ITN strategy varied by council had regional estimates of ITN access that diverged from the council-specific estimates. Predicted ITN access reached 60% only when “nets issued as a percentage of the council population” (NPP) exceeded 15%, and approached 80% ITN access when NPP was at or above 20%. Conclusion Modelling ITN access with country-specific net decay rates, council-level population, and ITN distribution data is a promising approach to monitor ITN coverage sub-regionally and between household surveys in Tanzania and beyond.

Abstract Background Threats to maintaining high population access with effective bed nets persist due to errors in quantification, bed net wear and tear, and inefficiencies in distribution activities. Monitoring bed net coverage is therefore critical, but usually occurs every 2–3 years through expensive, large-scale household surveys. Mobile phone-based survey methodologies are emerging as an alternative to household surveys and can provide rapid estimates of coverage, however, little research on varied sampling approaches has been conducted in sub-Saharan Africa. Methods A nationally and regionally representative cross-sectional mobile phone survey was conducted in early 2021 in Tanzania with focus on bed net ownership and access. Half the target sample was contacted through a random digit dial methodology (n = 3500) and the remaining half was reached through a voluntary opt-in respondent pool (n = 3500). Both sampling approaches used an interactive voice response survey. Standard RBM-MERG bed net indicators and AAPOR call metrics were calculated. In addition, the results of the two sampling approaches were compared. Results Population access (i.e., the percent of the population that could sleep under a bed net, assuming one bed net per two people) varied from a regionally adjusted low of 48.1% (Katavi) to a high of 65.5% (Dodoma). The adjusted percent of households that had a least one bed net ranged from 54.8% (Pemba) to 75.5% (Dodoma); the adjusted percent of households with at least one bed net per 2 de facto household population ranged from 35.9% (Manyara) to 55.7% (Dodoma). The estimates produced by both sampling approaches were generally similar, differing by only a few percentage points. An analysis of differences between estimates generated from the two sampling approaches showed minimal bias when considering variation across the indicator for households with at least one bed net per two de facto household population. Conclusion The results generated by this survey show that overall bed net access in the country appears to be lower than target thresholds. The results suggest that bed net distribution is needed in large sections of the country to ensure that coverage levels remain high enough to sustain protection against malaria for the population.

The purpose of this study was synthesizing mesoporous silica SBA-15 and investigated the effect of the initial temperature of the preparation surfactant using the hydrothermal process to synthesize silica SBA-15. Pluronic (P123) as surfactant template and TEOS as material precursor acted as a building block of the mesoporous silica material. Therefore, the interaction surfactant template and precursor during the hydrothermal process guided to silica SBA-15 properties. The results suggested that the physicochemical properties of these materials did not change significantly, but different condition temperature of surfactant and hydrothermal process affected the size of the specific surface area, pore volume, and pore size distribution. The largest specific surface area was 560 m² g-1, pore volume was 1.57 m³ g-1 and ordered pore size distribution around 11.24 nm after the initial temperature of the surfactant at 15°C and hydrothermal process at 100°C for 48 h. This resulted properties of SBA-15 are potentially applicable in various chemical and non-chemical based industries. [ABSTRACT FROM AUTHOR]

Invasive hemodynamic assessment of cardiac diseases has become an important diagnostic tool in recent decades. Non-invasive methods are the main techniques used to assess cardiac function, due to their wider availability. Cardiac catheterization is useful when there are diagnostic problems that cannot be solved with routine methods. Cardiac catheterization should be individualized according to the specific problems of the patient and based on the results from non-invasive methods. Invasive diagnostics is used in the assessment of patients with various cardiovascular diseases, including cardiomyopathies. In this review, we consider the role of cardiac catheterization, its advantages and disadvantages as part of the overall assessment of patients with cardiomyopathies.

Cardiomyopathies are a heterogeneous group of diseases. The main pathogenetic mechanism is myocardial damage due to genetic mutations. Cardiomyopathies are one of the leading causes of heart failure, sudden cardiac death, and life-threatening arrhythmias. Certain factors associated with poor prognosis determined the prognosis in this group of patients. Survival in different types of cardiomyopathies depends on the time of diagnosis and initial treatment. The types of cardiomyopathies discussed in this review are hypertrophic cardiomyopathy, dilative cardiomyopathy, restrictive cardiomyopathy, left ventricle non-compaction, and arrhythmogenic right ventricular cardiomyopathy.