Inhibition of KDM4 with QC6352 to Target High-Risk Neuroblastoma

Neuroblastoma (NB) is a malignancy of improperly maturated nerve tissues of the sympathetic nervous system. It is the most diagnosed extracranial solid tumor of childhood, and it accounts for roughly up to 10% of all childhood malignancies and 15% of all childhood malignancy-related deaths. MYCN amplification, occurring in 20-25% of all NB patients and 50% of all high-risk NB patients, is the well-characterized genetic abnormality and is associated with ill-fated outcomes. Regrettably, in spite of the contemporary therapeutic advances and aggressive combinatorial treatments, the overall 5-year event-free survival rate is roughly 51% with a 5-year overall survival rate of nearly 63%. Unfortunately, close to 50% of high-risk NB patients develop disease relapses, which are largely incurable with no salvageable therapies so far. Recent evidence highlights that NB exhibits two cellular heterogeneities, namely adrenergic (ADRN) and mesenchymal (MES), which are tightly controlled by core regulatory circuitry-transcription factors (CRC-TFs). Driven by super-enhancers, these CRC-TFs, produce interrelated, feed-forward transcriptional loops that ultimately reinforce a specific gene expression program that defines the cellular state and identity of the cell. We showed that histone lysine demethylase subfamily 4 (KDM4) protein expression was higher in MYCN-amplified (MNA) NB cell lines and patient-derived xenografts (PDXs) compared with non-MNA counterparts. Additionally, genetic depletion of KDM4 correlated with reduced proliferation in vitro and in vivo. Interestingly, forced MYCN overexpression in MES-dominant NB cells facilitated MES to ADRN cellular state shift that was accompanied by induction of KDM4 proteins. Through various functional and genetic assays, we further validated the importance of the MYCN/KDM4/ADRN CRC-TF axis in maintaining the ADRN cellular state of NB. In view of these thrilling results, we opted to expand the clinical utility and examine the prospect of pharmacologic inhibition of KDM4 with QC6352, a selective and potent KDM4 inhibitor. Our data depicted that monotherapy QC6352 was selectively sensitive against MNA NB cells in vitro. Additionally, monotherapy QC6352 depicted satisfactory antitumor activities in high-risk cell line-based xenografts (NB1691), PDXs, and TH-MYCN/ALKF1178L transgenic mouse model in vivo. Molecularly, QC6352 reduced the mRNA and protein levels of oncogenic drivers and various ADRN CRC-TFs. Interestingly, QC6352 also decreased KDM4 expression at the translational protein level. Additionally, QC6352 culminated in favorable anticancer effects in vitro and in vivo, reflected by differentiation induction, apoptosis instigation, DNA damage, cell cycle cessation, and interestingly type-I interferon reactivation. Epigenomic-based investigations utilizing assay for transposase-accessible chromatin with sequencing (ATAC-seq) showed QC6352 reduced chromatin accessibility of MYCN and ADRN CRC-TFs, whereas chromatin immunoprecipitation with sequencing (ChIP-seq) and cleavage under targets and tagmentation (CUT&TAG) analyses showed KDM4 proteins were bound to genomic loci of MYCN and ADRN CRC-TFs, and QC6352 treatment promoted induction of the transcriptional repressive H3K9me3 mark. Lastly, combination therapy comprising QC6352 and standard-of-care chemotherapeutics (vincristine and irinotecan) led to 100% complete response in MNA NB xenografts without overt toxicity and accompanied by prolongation of survival. All in all, this research offers a solid proof-of-concept that pharmacologic inhibition of KDM4 with QC6352 may be translated from bench to bedside as a novel therapeutic tactic for high-risk MNA NB patients. Moreover, two orthogonal drug screens comprising CRISPR-Cas9 knockout (metabolism and kinase libraries), and high-throughput PRISM analysis highlighted enhanced anticancer effects between QC6352 and mammalian target of rapamycin (mTOR) inhibition. We demonstrated that combination of QC6352 and some mTOR inhibitors resulted in enhanced anticancer effects in vitro in several MNA and non-MNA NB cells. Functional genetic assays to validate the enhanced anticancer effects between dual KDM4 and mTOR inhibition failed. Lastly, combination of QC6352+rapamycin did not result in enhanced anticancer effects in SKNAS xenografts in vivo. Unless more in vivo work is performed, the present findings do not provide a compelling motivation to combine QC6352 with mTOR inhibition in the treatment of NB tumors

ПИТАННЯ ЕКОНОМІЧНОЇ ДОСТУПНОСТІ ЛІКАРСЬКИХ ЗАСОБІВ НА АФРИКАНСЬКОМУ КОНТИНЕНТІ

ISSUES OF ECONOMIC AVAILABILITY OF MEDICAL DRUGS IN AFRICAO. Ievtushenko, Osama Abuzayid Mohamed Nur AhmedNational University of Pharmacy, Kharkiv city INTRODUCTIONCurrently Africa with its highest index of diseases in the world maintains a serious dependence of imported medical drugs. Imported production comprises from 80 to 100% in some African countries, despite the fact that the incomes of population and medical support system doesn’t correspond completely with the consumption of expensive medical drugs (further MD). There is an extremely severe problem of physical and economical availability of MD  in theEastern Mediterraneancountries. OBJECTIVE STATEMENT OF THE ARTICLEIn connection with the above mentioned, the purpose of the work is the analysis of economic availability of MD in theEastern Mediterraneancountries, and also  the comparison of the received indexes with the indexes of  European countries. In the researches it has been participated such countries as Sudan, Egypt, Lebanon, Uganda and Ethiopia. To compare the received indexes of availability and their level determination it has been made the comparison of indexes among themselves and also with the indexes of the developed country of the European continent. As a standard it has been taken Germany as a country with one of the most developed pharmaceutical markets in the world and the strongest health care system, which finances medical and pharmaceutical assurance among all the EU countries.RESEARCH METHODSIn this work it has been taken into account the pharma-economic  methods of analysis and methodology of the World Health Organization  (WHO) and Health Action International (HAI) «Prices determination of MD, their availability and price of components ", data obtained during this methodology examination [1, 4, 6-11]; information from regional and national sources [12]; and also the scientific publications on this topic [2,3,5]. Data concerning prices for medicines and the cost of treatment course were obtained in studying of retail prices in pharmacies of the above mentioned countries. In the total examination it has been studied the MD  which are used for the treatment of chronic diseases and which are included in the international list recommended for the continuous monitoring (study) by the World Health Organization . RESULTS AND IT DELIBERATION According to WHO recommendations, it has been selected the basic MD for the treatment of 14 the most common diseases, which will allow to make the international research. Also it is allowable to include in this list of MD the most important for the treatment of specific diseases in certain countries. Yes, for the African countries  such drugs are the remedies for the  malaria treatment.In the study it has been participated the generic MD sold at the lowest price. Further it has been determined the economic availability of studied MD, taking into account the ratio of the treatment cost by this drug (according to the  international treatment protocols) and the daily wage of unskilled low paid public officer in these countries.During the determination of economic accessibility of medicines it has been used the paying capacity adequacy ratio, which includes the lowest retail price of the drug (or the treatment course price), and the average salary for a certain period of time.The analysis shows that the availability of MD in some African countries is situated at the unsatisfactory level. Regarding the indicators of availability general perception, the lowest indicators hasSudan, the highest accessible indexes has Egypt. By comparison of the availability of MD in African countries and in Germany, for the diclofenac treatment course in Germany it is necessary to spend 0.24 of one day wages, and in Sudan - 5.3, which is higher in 22 times; for the paracetamol treatment the Sudan patients spend more in 10 times.Thus, the availability economic analysis of basic MD confirms  thatEgyptandLebanonassist a relatively low cost of basic MD, which is close to the level of the European countries. Especially in Egypt, the major part of economic availability indicators of medical drugs corresponds to parameters of the country with the developed pharmaceutical market and a strong health care system and this is Germany. Thus, the indicators ofEgyptare almost identical with those ofGermanyat the prices of Diclofenac, Atenolol, Captopril, Glibenclamide, Ceftriaxone, Diazepam, and even lower - with  Salbutamol, Amitriptyline, the antimalarial medical drugs.Thus, in Sudan is marked with the rather high prices and, consequently, low availability on a number of medical drugs such as Diclofenac, Paracetamol, Captopril, Simvastatin, Amitriptyline. Thus, patient inSudanneed  spend in 22 times more of money to the diclofenac treatment than patients inGermany. A treatment will paracetamol will be in10 times more expensive, treatment with captopril will be in 7 times more expensive. Comparison of availability indexes in theSudanwith the African region countries is also accompanied by a situation where the indicators availability of MD are in 3 - 10 times worse than in other countries with similar health care system. The necessity of  generic MD availability analyses, especially for the countries with the health care systems which are forming will help to make the fast and low priced  determination of the availability level of medicines for the population, the  timely reaction in case of indexes deterioration, the regulation of public policy of countries in the pricing field on MD as well as coordination of original and generic drugs use, which allow to reduce the budgetary costs of medical assistance without the quality loss.References1. Vyvchennya spozhyvannya likarsʹkykh zasobiv za anatomo-terapevtychno-khimichnoyu klasyfikatsiyeyu ta vstanovlenymy dobovymy dozamy (AT·S/DDD – metodolohiya): metod. rek. / A. M. Morozov, L. V. Yakovlyeva, A. V. Stepanenko ta in. – Kharkiv: Stylʹ-Yzdat. – 2013. – 34 s.2. Hromovyk B.P. Farmatsevtychnyy marketynh: teoretychni ta prykladni zasady / B.P. Hromovyk, H.D. Hasyuk, O.R. Levytsʹka. – Vinnytsya: Nova Knyha, 2004. – 464 s.3. Dovhun S. S. Otsenka stoymosty y ékonomycheskoy dostupnosty nootropnykh preparatov, naznachaemykh bolʹnym s ynsulʹtom / S.S. Dovhun // Sovremennye problemy nauky y obrazovanyya. – 2012. – № 2. – S. 33-39.4. Dumenko T. M. Vyvchennya dostupnosti osnovnykh likarsʹkykh zasobiv v Ukrayini: rezulʹtaty spilʹnoho proektu VOZ, NAI ta MOZ Ukrayiny / T. M. Dumenko, V. D. Pariy, L. B. Yakovleva, A. B. Zimenkovsʹkyy // Farmakoekonomika v Ukrayini: stan ta perspektyvy rozvytku: materialy VI naukovo-praktychnoyi konferentsiyi (m. Kharkiv, 22 lystopada 2013 r.) / redkol.: V.P. Chernykh ta in. – Kharkiv: Vyd-vo NFaU, 2013. – S. 180-181.5. Perehinetsʹ I. B. Dostupnistʹ osnovnykh likarsʹkykh zasobiv v Ukrayini: rezulʹtaty farmakoepidemiolohichnoho doslidzhennya (spilʹnyy proekt VOOZ, NAI ta MOZ Ukrayiny) / I. B. Perehinetsʹ, T. M. Dumenko. – Kyyiv, 23-24 zhovtnya 2013 roku. [Élektronnyy resurs]. – Rezhym dostupu: http://old.dec.gov.ua/site/file_uploads /ua/sem/7_rac_farm/4.pdf 6. Measuring medicine prices, availability, affordability and price components – 2ND edition. World Health Organization and Health Action International. – [Élektronnyy resurs]. – Rezhym dostupa:http://www.who.int/ medicines/areas/access/OMS_Medicine_prices.pdf 7. Database of medicine prices, availability, affordability and price components. [Élektronnyy resurs]. – Rezhym dostupa: http://www.haiweb.org/MedPriceDatabase/8. Medicine prices, availability, affordability & price components.Ukraine. Palliative care. [Élektronnyy resurs]. – Rezhym dostupa: http://www.haiweb.org/ medicineprices surveys/200709UAP/sdocs/EMP_Ukraine%20palliative%20Final.pdf9. Medicine prices, availability, affordability and price components. Ukraine. Survey date: March 2012. [Élektronnyy resurs]. – Rezhym dostupu: http://www.haiweb.org/medicineprices/surveys/201203UAE/sdocs/Summary_report_ukraine_mar2012.pdf 10. Medicine Prices, Availability, Affordability and Price Components in Sudan. Survey date: March 2012, Report date: April 2014. [Élektronnyy resurs]. – Rezhym dostupu: http://www.haiweb.org/medicineprices/surveys/201203SD /sdocs/Sudan_report_2012_FINAL.pdf 11. Medicine Prices, Availability and Affordability in Sudan. Report of a survey conducted in February – March 2013. [Élektronnyy resurs]. – Rezhym dostupu: [Elektronnyy resurs]. – Rezhym dostupu: http://www.haiweb.org/medicineprices /surveys/201302SD/sdocs/Sudan_survey_report_2013.pdf 12. Salah Ibrahim Kheder. Evaluating medicines prices, availability, affordability and price components inSudan / Salah Ibrahim Kheder, Hassan Mohamed Ali // Sudan Medical Monitor. – 2014. – Vol. 9, Issue 1. – P. 19-30

Safety and Efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Treatment options for Visceral Leishmaniasis (VL) in East Africa are far from satisfactory due to cost, toxicity, prolonged treatment duration or emergence of parasite resistance. Hence there is a need to explore alternative treatment protocols such as miltefosine alone or in combinations including miltefosine, sodium stibogluconate (SSG) or liposomal amphotericin B. The aim of this trial is to identify regimen(s) which are sufficiently promising for future trials in East Africa.</p> <p>Methods/Design</p> <p>A phase II randomized, parallel arm, open-labelled trial is being conducted to assess the efficacy of each of the three regimens: liposomal amphotericin B with SSG, Liposomal amphotericin B with miltefosine and miltefosine alone. The primary endpoint is cure at day 28 with secondary endpoint at day 210 (6 months). Initial cure is a single composite measure based on parasitologic evaluation (bone marrow, spleen or lymph node aspirate) and clinical assessment. Repeated interim analyses have been planned after recruitment of 15 patients in each arm with a maximum sample size of 63 for each. These will follow group-sequential methods (the triangular test) to identify when a regimen is inadequate (<75% efficacy) or adequate (>90% efficacy). We describe a method to ensure consistency of the sequential analysis of day 28 cure with the non-sequential analysis of day 210 cure.</p> <p>Discussion</p> <p>A regimen with adequate efficacy would be a candidate for treatment of VL with reasonable costs. The design allows repeated testing throughout the trial recruitment period while maintaining good statistical properties (Type I & II error rates) and reducing the expected sample sizes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01067443">NCT01067443</a></p

Prevalence, Awareness, Treatment, and Control of Hypertension among Saudi Adult Population: A National Survey

This cross-sectional study aimed at estimating prevalence, awareness, treatment, control, and predictors of hypertension among Saudi adult population. Multistage stratified sampling was used to select 4758 adult participants. Three blood pressure measurements using an automatic sphygmomanometer, sociodemographics, and antihypertensive modalities were obtained. The overall prevalence of hypertension was 25.5%. Only 44.7% of hypertensives were aware, 71.8% of them received pharmacotherapy, and only 37.0% were controlled. Awareness was significantly associated with gender, age, geographical location, occupation, and comorbidity. Applying drug treatment was significantly more among older patients, but control was significantly higher among younger patients and patients with higher level of physical activity. Significant predictors of hypertension included male gender, urbanization, low education, low physical activity, obesity, diabetes, and hypercholesterolemia. In conclusion prevalence is high, but awareness, treatment, and control levels are low indicating a need to develop a national program for prevention, early detection, and control of hypertension

The effect of alpha-lipoic acid supplementation on anthropometric, glycemic, lipid, oxidative stress, and hormonal parameters in individuals with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials

This systematic review and meta-analysis aimed to examine the effect of the antioxidant alpha-lipoic acid (ALA) on various cardiometabolic risk factors and hormonal parameters in patients with polycystic ovary syndrome (PCOS). We searched PubMed, EMBASE, SCOPUS, Cochrane Library, and Web of Science databases without language restrictions until May 2023 to find randomized controlled trials (RCTs) that assessed the impact of ALA supplementation on anthropometric, glycemic, lipid, oxidative stress, and hormonal parameters in women with PCOS. Outcomes were summarized using the standardized mean difference (SMD) and 95% confidence interval (CI) in a random-effects model. An I2 statistic of >60% established significant between-study heterogeneity. The overall certainty of the evidence for each outcome was determined using the grading of recommendations, assessment, development, and evaluations system. Seven RCTs met the inclusion criteria. The ALA group had significant reductions in fasting blood sugar (fasting blood sugar (FBS), n=7 RCTs, SMD, −0.60; 95% CI, −1.10 to −0.10; I2=63.54%, moderate certainty of evidence) and homeostatic model assessment for insulin resistance (homeostatic model assessment of insulin resistance (HOMA-IR), n=4 RCTs, SMD, −2.03; 95% CI, −3.85 to −0.20; I2=96.32%, low certainty of evidence) compared with the control group. However, significant differences were observed between the groups in body mass index, insulin, estrogen, follicle-stimulating hormone, luteinizing hormone, testosterone, low-density lipoprotein, high-density lipoprotein, triglyceride, total cholesterol, malondialdehyde, or total antioxidant capacity profiles. ALA supplementation improves FBS and HOMA-IR levels in women with PCOS. ALA consumption is an effective complementary therapy for the management of women with PCOS

Sodium Stibogluconate (SSG) & Paromomycin Combination Compared to SSG for Visceral Leishmaniasis in East Africa: A Randomised Controlled Trial

Visceral leishmaniasis (VL) is a parasitic disease with about 500,000 new cases each year and is fatal if untreated. The current standard therapy involves long courses, has toxicity and there is evidence of increasing resistance. New and better treatment options are urgently needed. Recently, the antibiotic paromomycin (PM) was tested and registered in India to treat this disease, but the same dose of PM monotherapy evaluated and registered in India was not efficacious in Sudan. This article reports the results of a clinical trial to test the effectiveness of injectable PM either alone (in a higher dose) or in combination with sodium stibogluconate (SSG) against the standard SSG monotherapy treatment in four East African countries—Sudan, Kenya, Ethiopia and Uganda. The study showed that the combination of SSG &PM was as efficacious and safe as the standard SSG treatment, with the advantages of being cheaper and requiring only 17 days rather than 30 days of treatment. In March 2010, a WHO Expert Committee recommended the use of the SSG & PM combination as a first line treatment for VL in East Africa

Safety and efficacy of single dose versus multiple doses of AmBisome for treatment of visceral leishmaniasis in eastern Africa: a randomised trial.

BACKGROUND: Anti-leishmanial drug regimens that include a single dose AmBisome could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. METHODOLOGY: A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1-5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. PRINCIPAL FINDINGS: The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73-93%), 40% (95%CI 19-64%), and 58% (95%CI 41-73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. CONCLUSIONS: The tested AmBisome regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. TRIALS REGISTRATION: www.clinicaltrials.govNCT00832208

The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS

Background The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. Methods and analysis Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care. . .'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. Conclusions This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. Copyright

The evolving SARS-CoV-2 epidemic in Africa: insights from rapidly expanding genomic surveillance

Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence domestically, and highlight that local sequencing enables faster turnaround time and more regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and shed light on the distinct dispersal dynamics of Variants of Concern, particularly Alpha, Beta, Delta, and Omicron, on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve, while the continent faces many emerging and re-emerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century