Differences in symptom severity and quality of life among patients with cancer using conventional therapies with/without herbal medicines in Uganda: a cross-sectional study

Objective: Patients with cancer experience numerous symptoms related to cancer and treatment side effects that reduce their quality of life (QOL). Although herbal medicine (HM) is used to manage such symptoms by patients in sub-Saharan Africa, data on patients perceived clinical outcomes are limited. We compared differences in QOL and symptom severity between patients with cancer using HM plus conventional therapies (i.e., chemotherapy, hormonal therapy, radiotherapy, surgery) and those using conventional therapies alone. Methods: This cross-sectional study included patients with cancer aged \u3e18 years who were consecutively sampled and completed a researcher-administered questionnaire between December 2022 and January 2023. Specifically, data was collected using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the MD Anderson Symptom Inventory for Traditional Chinese Medicine (MDASI-TCM). Data were analyzed using descriptive statistics and chi-square and logistic regression analyses. Results: Of 400 participants (67.5% female), 49% (n=195) used HM plus conventional therapies and 51% (n=205) used conventional therapies alone. Most participants were aged \u3e38 years (73.3%; median age 47 years). A univariate analysis showed the HM plus conventional therapies group had better mean scores for most QOL and symptom severity measures than the conventional therapies alone group. However, only role functioning significantly differed (p=0.046) in the bivariate analysis. There were no statistically significant differences between the two groups after confounder adjustment for all others measures of symptom severity and QOL. Conclusion: HM plus conventional therapies may offer minimal benefits or differences for clinical outcomes among patients with cancer. However, our findings have clinical, research, and public health implications for Uganda and other sub-Saharan African settings

The HIFα-Stabilizing Drug Roxadustat Increases the Number of Renal Epo-Producing Sca-1+ Cells

Inhibition of the prolyl-4-hydroxylase domain (PHD) enzymes, leading to the stabilization of hypoxia-inducible factor (HIF) α as well as to the stimulation of erythropoietin (Epo) synthesis, is the functional mechanism of the new anti-anemia drug roxadustat. Little is known about the effects of roxadustat on the Epo-producing cell pool. To gain further insights into the function of PHD inhibitors, we characterized the abundance of mesenchymal stem cell (MSC)-like cells after roxadustat treatment of mice. The number of Sca-1+ mesenchymal cells following roxadustat treatment increased exclusively in the kidneys. Isolated Sca-1+ cells demonstrated typical features of MSC-like cells, including adherence to tissue culture plates, trilineage differentiation potential, and expression of MSC markers. Kidney-derived Sca-1+ MSC-like cells were cultured for up to 21 days. Within the first few days in culture, cells stabilized HIF-1α and HIF-2α and temporarily increased Epo production upon incubation in hypoxia. In summary, we have identified a Sca-1+ MSC-like cell population that is involved in renal Epo production and might contribute to the strong anti-anemic effect of the PHD inhibitor roxadustat

PHD2 is a regulator for glycolytic reprogramming in macrophages.

The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1 alpha (HIF-1 alpha) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macropha(g)e behavior

The Cercal Organ May Provide Singing Tettigoniids a Backup Sensory System for the Detection of Eavesdropping Bats

Conspicuous signals, such as the calling songs of tettigoniids, are intended to attract mates but may also unintentionally attract predators. Among them bats that listen to prey-generated sounds constitute a predation pressure for many acoustically communicating insects as well as frogs. As an adaptation to protect against bat predation many insect species evolved auditory sensitivity to bat-emitted echolocation signals. Recently, the European mouse-eared bat species Myotis myotis and M. blythii oxygnathus were found to eavesdrop on calling songs of the tettigoniid Tettigonia cantans. These gleaning bats emit rather faint echolocation signals when approaching prey and singing insects may have difficulty detecting acoustic predator-related signals. The aim of this study was to determine (1) if loud self-generated sound produced by European tettigoniids impairs the detection of pulsed ultrasound and (2) if wind-sensors on the cercal organ function as a sensory backup system for bat detection in tettigoniids. We addressed these questions by combining a behavioral approach to study the response of two European tettigoniid species to pulsed ultrasound, together with an electrophysiological approach to record the activity of wind-sensitive interneurons during real attacks of the European mouse-eared bat species Myotis myotis. Results showed that singing T. cantans males did not respond to sequences of ultrasound pulses, whereas singing T. viridissima did respond with predominantly brief song pauses when ultrasound pulses fell into silent intervals or were coincident with the production of soft hemi-syllables. This result, however, strongly depended on ambient temperature with a lower probability for song interruption observable at 21°C compared to 28°C. Using extracellular recordings, dorsal giant interneurons of tettigoniids were shown to fire regular bursts in response to attacking bats. Between the first response of wind-sensitive interneurons and contact, a mean time lag of 860 ms was found. This time interval corresponds to a bat-to-prey distance of ca. 72 cm. This result demonstrates the efficiency of the cercal system of tettigoniids in detecting attacking bats and suggests this sensory system to be particularly valuable for singing insects that are targeted by eavesdropping bats

Mechanistic insights into the translocation of full length HIV-1 Tat across lipid membranes

AbstractThe mechanism of how full length Tat (aa 1–86) crosses artificial lipid membranes was elucidated by means of fluorescence spectroscopy and fluorescence microscopy. It was shown that full length Tat (aa 1–86) neither forms pores in large unilamellar vesicles (LUVs) nor in giant unilamellar vesicles (GUVs) composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). In contrast, an N-terminally truncated Tat protein (aa 35–86) that lacks the structurally defined proline- and cysteine-rich region as well as the highly conserved tryptophan residue at position 11 generates pores in artificial POPC-membranes, through which a water-soluble dye up to a size of 10kDa can pass. By means of fluorescence microscopy, the transfer of fluorescently labeled full length Tat across POPC-bilayers was unambiguously visualized with a concomitant accumulation of the protein in the membrane interface. However, if the dye was attached to the protein, also pore formation was induced. The size of the pores was, however smaller than the protein size, i.e. the labeled protein with a mass of 11.6kDa passed the membrane, while a fluorescent dye with a mass of 10kDa was excluded from the vesicles' interior. The results demonstrate that pore formation is not the prime mechanism by which full length Tat crosses a membrane

Mobile cancer prevention and early detection outreach in Uganda: Partnering with communities toward bridging the cancer health disparities through “asset‐based community development model”

Abstract Background Communities in low‐income countries are characterized by limited access to cancer prevention and early detection services, even for the commonest types of cancer. Limited resources for cancer control are one of the contributors to cancer health disparities. We explored the feasibility and benefit of conducting outreaches in partnership with local communities using the “asset‐based community development (ABCD)” model. Methods We analyzed the quarterly Uganda cancer institute (UCI) community outreach cancer health education and screening output reported secondary data without individual identifiers from July 2016 to June 2019 to compare the UCI‐hospital‐based and community outreach cancer awareness and screening services based on the ABCD model. Results From July 2016 to June 2019, we worked with 107 local partners and conducted 151 outreaches. Of the total number of people who attended cancer health education sessions, 201 568 (77.9%) were reached through outreaches. Ninety‐two (95%) cancer awareness TVs and radio talk‐shows conducted were sponsored by local partners. Of the total people screened; 22 795 (63.0%) cervical, 22 014 (64.4%) breast, and 4904 (38.7%) prostate screening were reached through community outreach model. The screen‐positive rates were higher in hospital‐based screening except for Prostate screening; cervical, 8.8%, breast, 8.4%, prostate, 7.1% than in outreaches; cervical, 3.2%, breast, 2.2%, prostate, 8.2%. Of the screened positive clients who were eligible for precancer treatment like cryotherapy for treatment of precervical cancer lesions, thousands‐folds monetary value and productive life saved relative to the market cost of cancer treatment and survival rate in Uganda. When the total number of clients screened for cervical, breast, and prostate cancer are subjected to the incremental cost of specific screening, a greater portion (98.7%) of the outreach cost was absorbed through community partnership. Conclusions Outreaching and working in collaboration with communities as partners through asset‐based community development model are feasible and help in cost‐sharing and leverage for scarce resources to promote primary prevention and early detection of cancer. This could contribute to bridging the cancer health disparities in the target populations

Cardiomyocyte-Specific Transgenic Expression of Prolyl-4-Hydroxylase Domain 3 Impairs the Myocardial Response to Ischemia

Aims: The prolyl-4-hydroxylase domain (PHD) enzymes are representing novel therapeutic targets for ischemic tissue protection. Whereas the consequences of a knock out of the PHDs have been analyzed in the context of cardioprotection, the implications of PHD overexpression is unknown so far. Methods and Results: We generated cardiomyocyte-specific PHD3transgenic mice (cPhd3tg). Resting cPhd3tg mice did not show constitutive accumulation of HIF-1α or HIF-2α or changes in HIF target gene expression in the heart. Cardiac function was followed up for 14 months in these mice and found to be unchanged. After challenging the cPhd3tg mice with ligation of the left anterior descending artery, HIF-1α/-2α accumulation in the left ventricles was blunted. This was associated with a significantly increased infarct size of the cPhd3tg compared to wild type mice. Conclusion: Whereas overexpression of PHD3 in the resting state does not significantly influence cardiac function, it is crucial for the cardiac response to ischemia by affecting HIFα accumulation in the ischemic tissue

PHD2 is a regulator for glycolytic reprogramming in macrophages

The prolyl-4-hydroxylase domain (PHD) enzymes are regarded as the molecular oxygen sensors. There is an interplay between oxygen availability and cellular metabolism, which in turn has significant effects on the functionality of innate immune cells, such as macrophages. However, if and how PHD enzymes affect macrophage metabolism are enigmatic. We hypothesized that macrophage metabolism and function can be controlled via manipulation of PHD2. We characterized the metabolic phenotypes of PHD2-deficient RAW cells and primary PHD2 knockout bone marrow-derived macrophages (BMDM). Both showed typical features of anaerobic glycolysis, which were paralleled by increased pyruvate dehydrogenase kinase 1 (PDK1) protein levels and a decreased pyruvate dehydrogenase enzyme activity. Metabolic alterations were associated with an impaired cellular functionality. Inhibition of PDK1 or knockout of hypoxia-inducible factor 1α (HIF-1α) reversed the metabolic phenotype and impaired the functionality of the PHD2-deficient RAW cells and BMDM. Taking these results together, we identified a critical role of PHD2 for a reversible glycolytic reprogramming in macrophages with a direct impact on their function. We suggest that PHD2 serves as an adjustable switch to control macrophage behavior