Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H ϩ -Coupled Nutrient Carriers Coexpressed in the Small Intestine

ABSTRACT 5-Aminolevulinic acid (ALA) is a prodrug used in photodynamic therapy, fluorescent diagnosis, and fluorescent-guided resection because it leads to accumulation of the photosensitizer protoporphyrin IX (PpIX) in tumor tissues. ALA has good oral bioavailability, but high oral doses are required to obtain selective PpIX accumulation in colonic tumors because accumulation is also observed in normal gut mucosa. Structural similarities between ALA and GABA led us to test the hypothesis that the H ϩ -coupled amino acid transporter PAT1 (SLC36A1) will contribute to luminal ALA uptake. Radiolabel uptake and electrophysiological measurements identified PAT1-mediated H ϩ -coupled ALA symport after heterologous expression in Xenopus oocytes. The selectivity of the nontransported inhibitors 5-hydroxytryptophan and 4-aminomethylbenzoic acid for, respectively, PAT1 and the H ϩ -coupled di/tripeptide transporter PepT1 (SLC15A1) were examined. 5-Hydroxytryptophan selectively inhibited PAT1-mediated amino acid uptake across the brush-border membrane of the human intestinal (Caco-2) epithelium whereas 4-aminomethylbenzoic acid selectively inhibited PepT1-mediated dipeptide uptake. The inhibitory effects of 5-hydroxytryptophan and 4-aminomethylbenzoic acid were additive, demonstrating that both PAT1 and PepT1 contribute to intestinal transport of ALA. This is the first demonstration of overlap in substrate specificity between these distinct transporters for amino acids and dipeptides. PAT1 and PepT1 expression was monitored by reverse transcriptase-polymerase chain reaction using paired samples of normal and cancer tissue from human colon. mRNA for both transporters was detected. PepT1 mRNA was increased 2.3-fold in cancer tissues. Thus, increased PepT1 expression in colonic cancer could contribute to the increased PpIX accumulation observed. Selective inhibition of PAT1 could enhance PpIX loading in tumor tissue relative to that in normal tissue

The Concise Guide to PHARMACOLOGY 2023/24:Transporters

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p

NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies

Early Release Science of the exoplanet WASP-39b with JWST NIRCam

Measuring the metallicity and carbon-to-oxygen (C/O) ratio in exoplanet atmospheres is a fundamental step towards constraining the dominant chemical processes at work and, if in equilibrium, revealing planet formation histories. Transmission spectroscopy provides the necessary means by constraining the abundances of oxygen- and carbon-bearing species; however, this requires broad wavelength coverage, moderate spectral resolution, and high precision that, together, are not achievable with previous observatories. Now that JWST has commenced science operations, we are able to observe exoplanets at previously uncharted wavelengths and spectral resolutions. Here we report time-series observations of the transiting exoplanet WASP-39b using JWST's Near InfraRed Camera (NIRCam). The long-wavelength spectroscopic and short-wavelength photometric light curves span 2.0 - 4.0 $\mu$m, exhibit minimal systematics, and reveal well-defined molecular absorption features in the planet's spectrum. Specifically, we detect gaseous H$_2$O in the atmosphere and place an upper limit on the abundance of CH$_4$. The otherwise prominent CO$_2$ feature at 2.8 $\mu$m is largely masked by H$_2$O. The best-fit chemical equilibrium models favour an atmospheric metallicity of 1-100$\times$ solar (i.e., an enrichment of elements heavier than helium relative to the Sun) and a sub-stellar carbon-to-oxygen (C/O) ratio. The inferred high metallicity and low C/O ratio may indicate significant accretion of solid materials during planet formation or disequilibrium processes in the upper atmosphere.Comment: 35 pages, 13 figures, 3 tables, Nature, accepte

WASP-193b: An extremely low-density super-Neptune

peer reviewe

WASP-193b: An extremely low-density super-Neptune

Gas giants transiting bright nearby stars are stepping stones for our understanding of planetary system formation and evolution mechanisms. This paper presents a particularly interesting new specimen of this kind of exoplanet discovered by the WASP-South transit survey, WASP-193b. This planet completes an orbit around its Vmag = 12.2 F9 main-sequence host star every 6.25 d. Our analyses found that WASP-193b has a mass of Mp = 0.139 +/- 0.029 M_Jup and a radius of Rp = 1.464 +/- 0.058 R_ Jup, translating into an extremely low density of rhop = 0.059 +\- 0.014 g/cm^3. The planet was confirmed photometrically by the 0.6-m TRAPPIST-South, the 1.0-m SPECULOOS-South telescopes, and the TESS mission, and spectroscopically by the ESO-3.6-m/HARPS and Euler-1.2-m/CORALIE spectrographs. The combination of its large transit depth (dF~1.4 %), its extremely-low density, its high-equilibrium temperature (Teq = 1254 +/- 31 K), and the infrared brightness of its host star (magnitude Kmag=10.7) makes WASP-193b an exquisite target for characterization by transmission spectroscopy (transmission spectroscopy metric: TSM ~ 600). One single JWST transit observation would yield detailed insights into its atmospheric properties and planetary mass, within ~0.1 dex and ~1% (vs ~20% currently with radial velocity data) respectively

Estimating the burden of selected non-communicable diseases in Africa: a systematic review of the evidence

Background The burden of non-communicable diseases (NCDs) is rapidly increasing globally, and particularly in Africa, where the health focus, until recently, has been on infectious diseases. The response to this growing burden of NCDs in Africa has been affected owing to a poor understanding of the burden of NCDs, and the relative lack of data and low level of research on NCDs in the continent. Recent estimates on the burden of NCDs in Africa have been mostly derived from modelling based on data from other countries imputed into African countries, and not usually based on data originating from Africa itself. In instances where few data were available, estimates have been characterized by extrapolation and over-modelling of the scarce data. It is therefore believed that underestimation of NCDs burden in many parts of Africa cannot be unexpected. With a gradual increase in average life expectancy across Africa, the region now experiencing the fastest rate of urbanization globally, and an increase adoption of unhealthy lifestyles, the burden of NCDs is expected to rise. This thesis will, therefore, be focussing on understanding the prevalence, and/or where there are available data, the incidence, of four major NCDs in Africa, which have contributed highly to the burden of NCDs, not only in Africa, but also globally. Methods I conducted a systematic search of the literature on three main databases (Medline, EMBASE and Global Health) for epidemiological studies on NCDs conducted in Africa. I retained and extracted data from original population-based (cohort or cross sectional), and/or health service records (hospital or registry-based studies) on prevalence and/or incidence rates of four major NCDs in Africa. These include: cardiovascular diseases (hypertension and stroke), diabetes, major cancer types (cervical, breast, prostate, ovary, oesophagus, bladder, Kaposi, liver, stomach, colorectal, lung and non-Hodgkin lymphoma), and chronic respiratory diseases (chronic obstructive pulmonary disease (COPD) and asthma). From extracted crude prevalence and incidence rates, a random effect meta-analysis was conducted and reported for each NCD. An epidemiological model was applied on all extracted data points. The fitted curve explaining the largest proportion of variance (best fit) from the model was further applied. The equation generated from the fitted curve was used to determine the prevalence and cases of the specific NCD in Africa at midpoints of the United Nations (UN) population 5-year age-group population estimates for Africa. Results From the literature search, studies on hypertension had the highest publication output at 7680, 92 of which were selected, spreading across 31 African countries. Cancer had 9762 publications and 39 were selected across 20 countries; diabetes had 3701 publications and 48 were selected across 28 countries; stroke had 1227 publications and 19 were selected across 10 countries; asthma had 790 publications and 45 were selected across 24 countries; and COPD had the lowest output with 243 publications and 13 were selected across 8 countries. From studies reporting prevalence rates, hypertension, with a total sample size of 197734, accounted for 130.2 million cases and a prevalence of 25.9% (23.5, 34.0) in Africa in 2010. This is followed by asthma, with a sample size of 187904, accounting for 58.2 million cases and a prevalence of 6.6% (2.4, 7.9); COPD, with a sample size of 24747, accounting for 26.3 million cases and a prevalence of 13.4% (9.4, 22.1); diabetes, with a sample size of 102517, accounting for 24.5 million cases and a prevalence of 4.0% (2.7, 6.4); and stroke, with a sample size of about 6.3 million, accounting for 1.94 million cases and a prevalence of 317.3 per 100000 population (314.0, 748.2). From studies reporting incidence rates, stroke accounted for 496 thousand new cases in Africa in 2010, with a prevalence of 81.3 per 100000 person years (13.2, 94.9). For the 12 cancer types reviewed, a total of 775 thousand new cases were estimated in Africa in 2010 from registry-based data covering a total population of about 33 million. Among women, cervical cancer and breast cancer had 129 thousand and 81 thousand new cases, with incidence rates of 28.2 (22.1, 34.3) and 17.7 (13.0, 22.4) per 100000 person years, respectively. Among men, prostate cancer and Kaposi sarcoma closely follows with 75 thousand and 74 thousand new cases, with incidence rates of 14.5 (10.9, 18.0) and 14.3 (11.9, 16.7) per 100000 person years, respectively. Conclusion This study suggests the prevalence rates of the four major NCDs reviewed (cardiovascular diseases (hypertension and stroke), diabetes, major cancer types, and chronic respiratory diseases (COPD and asthma) in Africa are high relative to global estimates. Due to the lack of data on many NCDs across the continent, there are still doubts on the true prevalence of these diseases relative to the current African population. There is need for improvement in health information system and overall data management, especially at country level in Africa. Governments of African nations, international organizations, experts and other stakeholders need to invest more on NCDs research, particularly mortality, risk factors, and health determinants to have evidenced-based facts on the drivers of this epidemic in the continent, and prompt better, effective and overall public health response to NCDs in Africa

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival