bluuebunny/crossref_metadata_2025 huggingface dataset:
AIXI Responses to Newcomblike Problems
Authors: Zagami Davide
Published: June 2020

We provide a rigorous analysis of AIXI's behaviour under repeated Newcomblike settings. In this context, a Newcomblike problem is a setting where an agent is tied against an environment that contains a perfect predictor, whose predictions are used to determine the environmet's outputs. Since AIXI lacks good convergence properties, we chose to focus the analysis on determining whether an environment appears computable to AIXI, that is, if it maps actions to observations in a way that a computable program can achieve. It is in this sense that, it turns out, AIXI can learn to one-box in *repeated* Opaque Newcomb, and to smoke in *repeated* Smoking Lesion, but may fail all other Newcomblike problems, because we found no way to reduce them in a computable form. However, we still suspect that AIXI can succeed in the repeated settings.
Model of Increasing Experiences Mathematics Learning with Group Method Project
Authors: Syah Rahmad , Husein Ismail
Published: June 2020

Improving student learning experience is a very important thing. purpose research to develop a group project method model. This study uses the experimental method by testing the experimental class and comparing conventional based learning and learning using the group project method. The results of this study indicate that using this group project method can improve student learning outcomes and learning experiences.
Load Balancing for Sharded Blockchains
Authors: Okanami Naoya , Nakamura Ryuya , Nishide Takashi
Published: June 2020

Sharding is an approach to designing a highly scalable blockchain. A sharded blockchain achieves parallelism by dividing consensus nodes (validators) into groups called shards and making them process different transactions in each shard. In this paper, we economically analyze users’ behavior on sharded blockchains and identify a phenomenon that users’ accounts and smart contracts eventually get concentrated in a few shards, making shard loads unfair. This phenomenon leads to bad user experiences, such as delays in transaction inclusions and increased transaction fees. To solve the above problem, we propose a load balancing ramework in sharded blockchains in which accounts and contracts are frequently reassigned into shards to reduce the difference of loads between shards. We formulate the contract reassignment as an optimization problem and present the algorithm to solve it. Further, we apply the framework to an existing sharding design (Ethereum 2.0) and modify the protocol to do load balancing. Finally, we simulate the protocol and observe smaller transaction delays and fees.
Mechanistic understanding and holistic approach of phytoremediation: A review on application and future prospects
Authors: Muungo Lungwani
Published: June 2020

Rapid industrialisation, increased rate of waste production, higher agricultural inputs, mining, industrial waste,and contaminated irrigation water are increasing the heavy metal contamination in agricultural land andfreshwater sources. These heavy metals contaminated resources are used by humans for food production thatultimately get accumulated in the food chain. Biomagnification of heavy metals can pose solemn health threatsto human life, such as mutations, endocrine disruption, nephro-toxicity, etc. There has long been a need fordecontamination of these resources and prevention from the further contamination to avert the negative effectson human health. The “phytoremediation” process is a very promising and eco-friendly approach for heavymetal remediation from contaminated sites with some limitations. An effort has been made to present thescattered information of phytoremediation technique in a single paper through this review. The present reviewdescribes the fundamentals of phytoremediation including the different associated processes, mechanism, andinfluencing factors. The mechanism of tolerance and detoxification of heavy metals by plants has also beendiscussed in brief. The possible amelioration/modification of a particular phytoremediation strategy has beenadvocated to increase its potential efficacy and further development of these strategies for future reference. Thereview tries to cover all the essential and adequate information of the relevant published data with some recentadvances in phytoremediation approaches. It is recommended to apply the combination of different availabletechniques or phytoremediation techniques with modern chemical, biological and genetic engineering tools foran easy and effective decontamination of heavy metals from soil and agricultural land. The review advocates thedevelopment of site specific, farmer driven, sequential and phytoremediation strategies along with policy supportfor effective decontamination.
Stable and radioactive cesium: A review about distribution in the environment, uptake and translocation in plants, plant reactions and plants' potential for bioremediation
Authors: Muungo Lungwani
Published: June 2020

Radiocesiumin water, soil, and air represents a severe threat to human health and the environment. It either actsdirectly on living organisms from external sources, or it becomes incorporated through the food chain, or both.Plants are at the base of the food chain; it is therefore essential to understand the mechanisms of plants for cesiumretention and uptake. In this review we summarize investigations about sources of stable and radioactive cesiumin the environment and harmful effects caused by internal and external exposure of plants to radiocesium.Uptake of cesiuminto cells occurs through molecular mechanisms such as potassiumand calciumtransporters inthe plasma membrane.In soil, bioavailability of cesiumdepends on the chemical composition of the soil and physical factors such as pH,temperature and tilling as well as on environmental factors such as soil microorganisms. Uptake of cesiumoccursalso from air through interception and absorption on leaves and from water through the whole submerged surface.We reviewed information about reducing cesium in the vegetation by loss processes, and we extractedtransfer factors from the available literature and give an overview over the uptake capacities of 72 plants for cesiumfrom the substratum to the biomass. Plants with high uptake potential could be used to remediate soil andwater from radiocesium by accumulation and rhizofiltration. Inside plants, cesium distributes fast between thedifferent plant organs and cells, but cesiumin soil is extremely stable and remains for decades in the rhizosphere.Monitoring of contaminated soil therefore has to continue for many decades, and edible plants grown on suchsoil must continuously be monitored.
Safety and acceptability of silicone elastomer vaginal rings as potential microbicide delivery method in African women
Authors: Muungo Lungwani
Published: June 2020

Background: Vaginal rings are a long-acting dosage form in development for delivery of HIV microbicides. Rings have been marketed in the US and Europe since the mid 1990s for menopausal symptoms and since 2002 for contraception; however, African women, a target population for HIV microbicides, have limited experience with vaginal rings.Methods: A crossover, safety and acceptability study was conducted in healthy, sexually active women at 3 research centers in South Africa and 1 in Tanzania. Women were randomized 1:1 to a placebo vaginal ring for 12 weeks, followed by a 12-week no treatment observation period, or vice versa. Safety was assessed by colposcopy, adverse events, and laboratory assessments. Ring acceptability and adherence were assessed by questionnaires.Results: Of 169 women, 85% completed the study. Ring expulsions and removals were reported by 10% and 11% of participants, respectively. The most common reason for both expulsion and removal was menses related. In most cases (64%), the ring was washed and re-inserted. Eighty-two percent of participants reported no ring removals for the duration of the trial, and 99% of women reported wearing the ring for at least 80% of the time. Male partner interviews indicated that men did not feel the ring during intercourse, that it did not impact their sexual pleasure, and that they did not suffer any side effects from the rings. Ninety-five percent of women found the ring to be very comfortable. Vaginal candidiasis was the most common adverse event, occurring in 11% of women during each period. Vaginal discharge (2%), vaginal odor (2%), and bacterial vaginitis (2%) were assessed as possibly or probably related to the ring, and occurred with similar frequency in the observation period. One SAE of appendicitis was assessed as probably not related to the ring. Thirty-four percent of participants had STIs at screening, and 12% had STIs at the crossover and final study visits. Three participants (2%) tested HIV positive during the study, two at the crossover visit and one at the final visit. All questionnaire responders were willing to use the vaginal ring if shown to be effective for HIV prevention.Conclusions: The vaginal ring was safe and well tolerated for 12 weeks in African women. Participant removal of the ring for menses and cleaning indicates a need for enhanced adherence counseling. All study participants found the ring acceptable and would use it if shown to prevent HIV infection.
Therapeutic Outcomes in AIDS-Associated Kaposi's Sarcoma Patients on Antiretroviral Therapy Treated with Chemotherapy at Two Tertiary Hospitals in Lusaka, Zambia
Authors: Muungo Lungwani
Published: June 2020

The incidence of HIV-associated Kaposi’s sarcoma (KS) remains high in Zambia in theantiretroviral therapy era. The most efficacious treatment regimen for KS has yet to be established.In both developed and developing countries, treatment regimens have had limited efficacy. Latepresentation in Africa affects therapeutic outcomes.Objective: The aim of this study was to determine therapeutic outcomes of epidemic KS patients oncombination antiretroviral therapy (cART) after completion of six cycles of Adriamycin, Bleomycin,and Vincristine (ABV) chemotherapy.Methods: This was a descriptive cross-sectional study. Study participants were drawn from a studydatabase of confirmed incident KS patients seen at the Skin Clinic of the University Teaching Hospitals(UTH) during the period between August, 2015 and September, 2016.Results: Of the 38 successfully recruited study participants, a complete response was documented in18 (47%) after 6 cycles of ABV whereas 20 (53%) experienced a partial response. KS recurrencewas observed in 8 (44%) of the individuals that experienced an initial complete response. At the timeof the study, clinical assessment revealed that KS lesions had completely regressed in 21 (55%) ofall the patients.Conclusion: ABV chemotherapy appears ineffective in long-term resolution of epidemic KS patientson ART. Recurrence rates are high after chemotherapy in patients that experience initially favorableresponses to treatment. There is a need to diagnose KS earlier, and to develop more efficacioustreatment options in order to reduce recurrence rates for epidemic KS.Keywords: Kaposi’s Sarcoma, HIV-associated, treatment, chemotherapy, outcomes, recurrence.
Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer.
Authors: Muungo Lungwani
Published: June 2020

Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecularmechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocytegrowth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediatingestrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependenttissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expressionpatterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies andnonradioactive in situ hybridization with T–T dimerized synthetic oligonucleotide probes. We next comparedthe results with the expression of estrogen receptor (ER) a and b, proliferative activity and apoptotic frequency(TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ERpositive(MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In thesurgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), whileKGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis ofboth KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated withthe expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNELindex, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detectedonly in ER a-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect ofKGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate thatER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, inhuman breast cancer.
Compound A inhibits bladder cancer growth predominantly via glucocorticoid receptor transrepression.
Authors: Muungo Lungwani
Published: June 2020

Recent evidence indicates that glucocorticoids (GCs) suppress bladder cancer cell invasion throughthe GC receptor (GR) pathway, whereas androgen-mediated androgen receptor (AR) signals inducebladder tumor progression. In this study, we assessed the effects of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (compound A [CpdA]), which was shown to function asnot only a GR modulator but also an AR antagonist, on the growth of bladder cancer. In GR/ARpositivecells, CpdA strongly inhibited cell proliferation and colony formation as well as increasedG1 phase-arrested cell population and apoptosis. Specifically, CpdA at 1?Mdecreased cell viabilityof TCCSUP/UMUC3-control-short hairpin RNA (shRNA), TCCSUP/UMUC3-GR-shRNA, and TCCSUP/UMUC3-AR-shRNA by 50%/67%, 25%/26%, and 38%/58%, respectively. CpdA also inhibited cellmigration and invasion of GR/AR-positive (up to 61% decrease) and GR-positive/AR-silencing (upto 51% decrease) lines and, less strongly, those of GR-silencing/AR-positive lines (up to 35%decrease). Additionally, in UMUC3-control xenograft-bearing male mice, CpdA more stronglysuppressed tumor growth than dexamethasone or hydroxyflutamide. In reporter gene assays,CpdA failed to induce GR transactivation, whereas it antagonized dihydrotestosterone-enhancedAR transactivation. In contrast, CpdA reduced nuclear factor (NF)-?B and activator protein 1transcriptional activities, indicating induction of GR-mediated transrepression. Correspondingly,the expression of NF-?B-related molecules, matrix metalloproteinase-2, matrix metalloproteinase-9, interleukin-6, and vascular endothelial growth factor, was significantly down-regulatedby CpdA in control lines but not in GR-silencing cells. Moreover, coimmunoprecipitation showedthat CpdA promoted the interactions between GR and NF-?B. Thus, CpdA likely inhibits bladdercancer growth predominantly via inducing GR transrepression and at least partially mediatedthrough the AR pathway, suggesting its effects more beneficial than GCs/pure GR ligands or ARantagonists. (Molecular Endocrinology 29: 1486–1497, 2015)
The emerging role of noncoding RNA in prostate cancer progression and its implication on diagnosis and treatment
Authors: Muungo Lungwani
Published: June 2020

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncodingRNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAsand long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgenand its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition,progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis ofAR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptionallevel. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression.This review focused on the role of various ncRNAs in prostate cancer and the association between their expression andCRPC.
Impaired Estrogen Sensitivity in Bone by Inhibiting Both Estrogen Receptor a and b Pathways*
Authors: Muungo Lungwani
Published: June 2020

Although it is well established that estrogen deficiencycauses osteoporosis among the postmenopausalwomen, the involvement of estrogen receptor (ER) in itspathogenesis still remains uncertain. In the presentstudy, we have generated rats harboring a dominantnegative ERa, which inhibits the actions of not only ERabut also recently identified ERb. Contrary to our expectation,the bone mineral density (BMD) of the resultingtransgenic female rats was maintained at the same levelwith that of the wild-type littermates when sham-operated.In addition, ovariectomy-induced bone loss wasobserved almost equally in both groups. Strikingly, however,the BMD of the transgenic female rats, after ovariectomized,remained decreased even if 17b-estradiol(E2) was administrated, whereas, in contrast, the decreaseof littermate BMD was completely prevented byE2. Moreover, bone histomorphometrical analysis ofovariectomized transgenic rats revealed that the higherrates of bone turnover still remained after treatmentwith E2. These results demonstrate that the preventionfrom the ovariectomy-induced bone loss by estrogen ismediated by ER pathways and that the maintenanceof BMD before ovariectomy might be compensatedby other mechanisms distinct from ERa and ERbpathways.
Expression of Androgen and Estrogen Signaling Components and Stem Cell Markers to Predict Cancer Progression and Cancer-Specific Survival in Patients with Metastatic Prostate Cancer
Authors: Muungo Lungwani
Published: June 2020

Purpose: Genes of androgen and estrogen signaling cells and stem cell–like cells play crucial roles inprostate cancer. This study aimed to predict clinical failure by identifying these prostate cancer-related genes.Experimental Design: We developed models to predict clinical failure using biopsy samples from atraining set of 46 and an independent validation set of 30 patients with treatment-na€?ve prostate cancer withbone metastasis. Cancerous and stromal tissues were separately collected by laser-captured microdissection.We analyzed the association between clinical failure andmRNAexpression of the following genes androgenreceptor (AR) and its related genes (APP, FOX family, TRIM 36, Oct1, and ACSL 3), stem cell–like molecules(Klf4, c-Myc, Oct 3/4, and Sox2), estrogen receptor (ER), Her2, PSA, and CRP.Results: Logistic analyses to predict prostate-specific antigen (PSA) recurrence showed an area under thecurve (AUC) of 1.0 in both sets for Sox2, Her2, and CRP expression in cancer cells, AR and ERa expression instromal cells, and clinical parameters. We identified 10 prognostic factors for cancer-specific survival (CSS):Oct1, TRIM36, Sox2, and c-Myc expression in cancer cells; AR, Klf4, and ERa expression in stromal cells; andPSA, Gleason score, and extent of disease.Onthe basis of these factors, patients were divided into favorable-,intermediate-, and poor-risk groups according to the number of factors present. Five-year CSS rates for the 3groups were 90%, 32%, and12%in the training set and 75%, 48%, and0%in the validation set, respectively.Conclusions: Expression levels of androgen- and estrogen signaling components and stem cell markersare powerful prognostic tools.
Acceptability of tenofovir gel as a vaginal microbicide among women in a phase I trial a mixed-methods study,
Authors: Muungo Lungwani
Published: June 2020

THE GLOBAL HIV EPIDEMIC increasingly affectswomen.1 For most, the only risk factor for becominginfected is the behavior of their male sexualpartners.1 Condoms often are unacceptableand insufficiently used,2–4 gender-based powerimbalances can make them difficult to negotiate,4–7 and religious beliefs, fertility needs, fear ofimplied infidelity, and preferences for sex withouta barrier are challenges to their acceptabilityand use. Women-initiated HIV prevention methodsare urgently needed, making the developmentof vaginal microbicides that reduce the likelihoodof sexual transmission of HIV a majorpublic health priority.First-generation vaginal microbicides will mostlikely be topical gels inserted into the vagina withan applicator. A variety of microbicides is currentlyunder development, and six have enteredlate-stage clinical trials.8–12 Initial product acceptabilityhas been assessed in clinical trials,13–16 surveysof product attributes among potentialusers17,18 and their partners,19 and studies that useover-the-counter (OTC) surrogates or placebo gelwith presumed similar formulation and applicationcharacteristics as eventual products.20–23 Acceptabilityassessments in early clinical trials areespecially important because their findings can influencefurther development of the product.Here, we report on acceptability data amongwomen participating in a phase I trial of tenofovirgel, a candidate microbicide that inhibits HIV reversetranscriptase. Details of the trial are reportedelsewhere,24 as is acceptability amongmale partners of trial participants.25 This was thefirst human trial of a topical antiretroviral thatspecifically inhibits a necessary replication stepin the HIV life cycle. Interest in this approach toHIV prevention has increased in recent yearssince efficacy trials of a topical surfactant(nonoxynyl-9) and a nonspecific inhibitor of HIVbinding (cellulose sulfate) indicated that thesetwo types of compounds were not protective andpotentially increased HIV transmission in womenwho had frequent sexual exposures to HIV. Severallarger-scale, expanded safety and proof-ofconcepttrials of tenofovir gel are now underway,based in part on the safety, tolerability, and acceptabilityof this microbicide demonstrated inthe study described in this paper.
Kru¨ ppel-like factor 5 in human breast carcinoma: a potent prognostic factor induced by androgens
Authors: Muungo Lungwani
Published: June 2020

Kru¨ ppel-like factor 5 (intestinal) or Kru¨ ppel-like factor 5 (KLF5) is a zinc finger-containingtranscription factor and involved in important biological processes including cell proliferation anddifferentiation. However, clinical significance of KLF5 protein has remained largely unknown inbreast cancer. Therefore, in this study, we immunolocalized KLF5 in 113 human breast carcinomacases. KLF5 immunoreactivity was frequently detected in the nuclei of breast carcinoma cells, andmedian value of the ratio of KLF5-positive carcinoma cells was 30% and was positively associatedwith the status of androgen receptor. KLF5 immunoreactivity was also significantly associated withincreased risk of recurrence and worse clinical outcome in breast cancer patients by univariateanalyses, and subsequent multivariate analyses demonstrated that KLF5 immunoreactivity was anindependent prognostic factor for both disease-free and breast cancer-specific survival of thepatients. We then examined possible regulation of KLF5 by androgen using MCF-7 breastcarcinoma cells. KLF5 mRNA was induced by biologically active androgen 5a-dihydrotestosteronein a dose- and time-dependent manner in MCF-7 cells. In addition, results of transfectionexperiments demonstrated that proliferation activity of MCF-7 cells was significantly associatedwith the KLF5 expression level. These findings suggest that KLF5 is an androgen-responsive genein humanbreast carcinomas and play important roles in the progression of breast carcinomas. KLF5immunoreactivity is therefore considered a potent prognostic factor in human breast cancers.Endocrine-Related Cancer (2012) 19 741–750
Prostaglandin receptors induce urothelial tumourigenesis as well as bladder cancer progression and cisplatin resistance presumably via modulating PTEN expression,
Authors: Muungo Lungwani
Published: June 2020

Background: We investigated the role of prostaglandin receptors (e.g. prostaglandin E2 receptor 2 (EP2), EP4) and the efficacy ofcelecoxib in urothelial tumourigenesis and cancer progression.Methods: We performed immunohistochemistry in bladder cancer (BC) tissue microarrays, in vitro transformation assay in anormal urothelial SVHUC line, and western blot/reverse transcription–polymerase chain reaction/cell growth assays in BC lines.Results: EP2/EP4 expression was elevated in BCs compared with non-neoplastic urothelial tissues and in BCs from those whowere resistant to cisplatin-based neoadjuvant chemotherapy. Strong positivity of EP2/EP4 in non-muscle-invasive tumours orpositivity of EP2/EP4 in muscle-invasive tumours strongly correlated with disease progression or disease-specific mortality,respectively. In SVHUC cells, exposure to a chemical carcinogen 3-methylcholanthrene considerably increased and decreased theexpression of EP2/EP4 and phosphatase and tensin homologue (PTEN), respectively. Treatment with selective EP2/EP4 antagonistor celecoxib also resulted in prevention in 3-methylcholanthrene-induced neoplastic transformation of SVHUC cells. In BC lines,EP2/EP4 antagonists and celecoxib effectively inhibited cell viability and migration, as well as augmented PTEN expression.Furthermore, these drugs enhanced the cytotoxic activity of cisplatin in BC cells. EP2/EP4 and PTEN were also elevated andreduced, respectively, in cisplatin-resistant BC sublines.Conclusions: EP2/EP4 activation correlates with induction of urothelial cancer initiation and outgrowth, as well aschemoresistance, presumably via downregulating PTEN expression.
Factors influencing adherence to antiretroviral therapy among people living with HIV in an urban and rural setting Tanzania
Authors: Muungo Lungwani
Published: June 2020

Adherence is one of the most crucial determinants of treatment response toantiretroviral therapy (ART). An analytical cross-sectional study was conducted in24 Care and Treatment Centres (CTC) in Dar es Salaam and Iringa regions inTanzania. Data was collected using questionnaire and appointments records. A totalof 943 patients attending at the care and treatment sites in Dar es Salaam and Iringawere recruited. Adherence based on keeping appointments and on four days recallwas 65% and 70%, respectively. Adherence based on taking ART more than 95% ofthe time in one month was 83%. Satisfaction with health services, having treatmentsupport, having knowledge on the use of ART, early presentation to CTC, and beingon ART for more than one year, were associated with good adherence. Being in theurban region, using traditional medicine, medicine side effects and alcoholconsumption problems negatively associated with adherence to ART.
The current status of infrastructure for monitoring the efficacy of antimalarial therapeutics in Zambia
Authors: Muungo Lungwani
Published: June 2020

Background. Sub-Saharan countries have experienced centuries of high morbidity and mortality due to malaria. In addition to insecticide-treated mosquito nets and indoor residual spraying, modern antimalarial medicines have been developed to reduce disease prevalence, although the emergence of drug-resistant strains has compromised their efficacy. The purpose of this study was to evaluate the current status of malaria diagnosis and treatment and to monitor the therapeutic efficacy of antimalarial drugs.Materials and Methods. A descriptive cross-sectional survey was conducted from 2011 to 2013 at 10 district hospitals in Zambia designated as malaria sentinel sites as well as at the National Malaria Control Centre. District medical officers at each site completed interview questionnaires.Results. Although basic infrastructure necessary for monitoring antimalarial drug resistance (such as laboratory, dispensary, admission ward, database unit, administration offices, bed space, examination and emergency rooms) was present at all sites, there was a shortage of licensed healthcare personnel. At some sites, antimalarial drugs were prescribed for malaria-like symptoms without diagnostic confirmation by blood smear. There was no regular monitoring of antimalarial drug resistance: only one trial was conducted among all sites in the previous 24 months.Conclusion. A lack of antimalarial drug resistance monitoring might be associated with personnel and funding shortages. Additional financial support would be necessary to avoid the development and spread of drug-resistant malaria in Zambia.
Vaginal Ring Adherence in Sub-Saharan Africa: Expulsion, Removal, and Perfect Use
Authors: Muungo Lungwani
Published: June 2020

In sub-Saharan Africa, HIV incidence andprevalence remain disproportionately high among women.Vaginal rings (VRs) have been formulated for the deliveryof antiretroviral-based microbicides, and their favorablesafety and tolerability profiles reported in clinical studies.Although the concept of drug release through a VR hasexisted since 1970, and VRs have been marketed since1992 for contraceptive or hormone replacement purposes,VR use as a microbicide delivery system is a novelapplication. This is the first study to evaluate VR adherenceamong African women in the context of its potential use asan HIV prevention method, to examine predictors ofadherence, and to describe clinical or contextual reasonsfor VR removals or nonadherence. This was a randomizedtrial of the safety and acceptability of a placebo VR wornfor 12 weeks in 170 HIV-negative, African women aged18–35 in four clinic sites in South Africa and Tanzania.The findings suggest that adherence to VR use in thecontext of HIV prevention trials in these communitiesshould be high, thereby enabling more accurate assessmentof an active microbicide safety and efficacy.Keywords Vaginal ring ? Adherence ? Sub-SaharanAfrica ? Female-controlled HIV prevention methods ?Microbicide delivery
TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma
Authors: Muungo Lungwani
Published: June 2020

TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression andits function in renal cell carcinoma (RCC) are still unknown. Here in this study, weinvestigated the clinical significance of TRIM44 and its biological function in RCC.TRIM44 overexpression was significantly associated with clinical M stage, histologictype (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028,respectively). Moreover, TRIM44 overexpression was significantly associated withpoor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function andloss-of-function studies using TRIM44 and siTRIM44 transfection showed thatTRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1and 769P. To further investigate the role of TRIM44 in RCC, we performed integratedmicroarray analysis in Caki1 and 769P cells and explored the data in the Oncominedatabase. Interestingly, FRK was identified as a promising candidate target gene ofTRIM44, which was downregulated in RCC compared with normal renal tissues. Wefound that cell proliferation was inhibited by TRIM44 knockdown and then recoveredby siFRK treatment. Taken together, the present study revealed the associationbetween high expression of TRIM44 and poor prognosis in
Designing preclinical perceptibility measures to evaluate topical vaginal gel formulations relating user sensory perceptions and experiences to formulation properties
Authors: Muungo Lungwani
Published: June 2020

The effectiveness of any biomedical prevention technology relies on both biological efficacy and behavioraladherence. Microbicide trials have been hampered by low adherence, limiting the ability to draw meaningfulconclusions about product effectiveness. Central to this problem may be an inadequate conceptualization of howproduct properties themselves impact user experience and adherence. Our goal is to expand the current microbicidedevelopment framework to include product ‘‘perceptibility,’’ the objective measurement of user sensoryperceptions (i.e., sensations) and experiences of formulation performance during use. For vaginal gels, a setof biophysical properties, including rheological properties and measures of spreading and retention, may criticallyimpact user experiences. Project LINK sought to characterize the user experience in this regard, and tovalidate measures of user sensory perceptions and experiences (USPEs) using four prototype topical vaginal gelformulations designed for pericoital use. Perceptibility scales captured a range of USPEs during the productapplication process (five scales), ambulation after product insertion (six scales), and during sexual activity (eightscales). Comparative statistical analyses provided empirical support for hypothesized relationships between gelproperties, spreading performance, and the user experience. Project LINK provides preliminary evidence for theutility of evaluating USPEs, introducing a paradigm shift in the field of microbicide formulation design. Wepropose that these user sensory perceptions and experiences initiate cognitive processes in users resulting inproduct choice and willingness-to-use. By understanding the impact of USPEs on that process, formulationdevelopment can optimize both drug delivery and adherence.
Sulindac enhances adenoviral vector expressing mda-7/IL-24–mediated apoptosis in human lung cancer
Authors: Muungo Lungwani
Published: June 2020

Several studies have shown antitumor activities of themelanoma differentiation–associated gene 7 (mda-7) andthe nonsteroidal anti-inflammatory drug sulindac whenused as a monotherapies against a wide variety of humancancers. However, the combined effects of mda-7 andsulindac have not previously been tested. Therefore, wetested the antitumor activity of an adenoviral vectorexpressing mda-7 (Ad-mda7) in combination with sulindacagainst non–small cell lung cancer cells in vitro andin vivo. When treated with Ad-mda7 in combination withsulindac, human lung cancer cells (A549 and H1299)underwent growth suppression resulting in apoptosis. Thegrowth inhibition induced by Ad-mda7 in combination withsulindac was significantly greater than that observed withAd-mda7 or sulindac alone. Furthermore, the degree ofgrowth inhibition induced using this combination wasdose-dependent for sulindac. Treatment with Ad-mda7 incombination with sulindac had no growth inhibitoryeffects on human normal lung (CCD-16) fibroblasts. Wethen investigated the mechanism by which sulindacenhances Ad-mda7-mediated apoptosis. Sulindac increasedexpression of ectopic MDA-7 protein in tumorcells, thereby increasing the expression of downstreameffectors RNA-dependent protein kinase, p38MAPK,caspase-9, and caspase-3 and enhancing apoptosis ofnon–small cell lung cancer cells. Pulse-chase experimentsshowed that the increased expression of MDA-7 protein insulindac-treated cells was due to increased half-life of theMDA-7 protein. Finally, treatment of human lung tumorxenografts in nude mice with Ad-mda7 plus sulindacsignificantly suppressed growth (P = 0.001) comparedwith Ad-mda7 or sulindac alone. Our results show for thefirst time that combined treatment with Ad-mda7 plussulindac enhances growth inhibition and apoptosis ofhuman lung cancer cells. The increased antitumor activityobserved with the combination treatment is a result ofincreased half-life of MDA-7 protein. Regulation of proteinturnover is a heretofore-unrecognized mechanism of thisnonsteroidal anti-inflammatory drug. [Mol Cancer Ther2005;4(2):291–304]
Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring
Authors: Muungo Lungwani
Published: June 2020

Breastfeeding (BF) women are an important population for biomedicalHIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirinevaginal ring (VR) reduced women’s risk of sexually transmitted HIV infection in twophase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, andBirmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who hadalready weaned their infants but were still able to express breast milk. Women wereinstructed to use the VR continuously for 14 days and provided milk, plasma, andcervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposedto the drug, but infant dosage was estimated according to FDA guidance. Adverseevents (AEs) were collected at all contacts. The study was completed with100% participant retention. Median dapivirine concentrations were 676 pg/ml inbreast milk, 327 pg/ml in plasma (milk/plasma ratio ?2.0), and 36.25 ng/mg in CVF.Six participants experienced 10 total AEs, none of which required VR discontinuation.The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first studyof dapivirine exposure during lactation, dapivirine VR use was associated with lowerconcentrations of detectable dapivirine in milk and plasma than in CVF samples anda favorable safety profile. Estimated daily levels of infant dapivirine exposure werealso low. Additional studies are needed to evaluate longer periods of dapivirine VRuse among BF mother-infant pairs living in regions with higher incidence of sexuallytransmitted HIV infection. (This study has been registered at ClinicalTrials.gov underregistration no. NCT02808949.)
Overgeneral and Specific Autobiographical Memory Predict the Course of Depression: An Updated Meta-Analysis
Authors: Hallford David John , Rusanov Danielle , Yeow Joseph , Barry Tom Joseph
Published: June 2020

Impairments in retrieving event-level, specific autobiographical memories, termed overgeneral memory (OGM) are recognised as a feature of clinical depression. A previous meta-analytic review (Sumner, Griffith, & Mineka, 2010) assessing how OGM predicts the course of subsequent depressive symptoms showed small, but robust effects for correlations and regression analyses when baseline depressive symptoms were controlled for. We aimed to update this study and examine whether their findings replicate given the decade of research that has been published since. A systematic literature review using the same eligibility criteria as the previous meta-analysis lead to a doubling of eligible studies (31 vs. 15). The results provided more precise estimates of effect sizes, and largely support the finding that OGM predicts the course of depressive symptoms. The effects were generally small, but significantly larger among clinical samples, compared to studies with non-clinical samples. Higher age was associated with stronger effects, while longer follow-up with associated with weaker effects. The findings on other moderating variables that were analysed were mixed. Continued research into this modifiable cognitive process may help to provide an avenue to better understand and treat highly prevalent and impactful depressive disorders.
BIOSYNTHESIS AND DEGRADATION OF STARCH IN HIGHER PLANTS
Authors: Muungo Lungwani
Published: June 2020

Numerous reviews on starch biosynthesis and degradation have appeared inthe 1980s (4, 23, 39, 40, 51, 73, 100, 101, 124, 125). Here we updateestablished concepts and emphasize three topics that we consider to now meritreexamination: the significance of enzyme multiplicity, a comparison ofdegradation of reserve and transitory starch, and the localization of starchdegrading enzymes in starch-free cellular compartments of leaf tissues. Westress the cell physiological aspects of starch metabolizing enzymes.
Efp as a primary estrogen‐responsive gene in human breast cancer.
Authors: Muungo Lungwani
Published: June 2020

We have previously isolated the efp (estrogenresponsivefinger protein) that is required for the normalestrogen-induced cell proliferation. Here, we show the genomicorganization of the human efp gene which consists of nine exons.The efp mRNA was expressed in human breast tumors and theestrogen-induced expression of the efp was found in MCF-7human breast cancer cells. Moreover, efp promoter activity wasenhanced through the estrogen-responsive element dependent onestrogen and estrogen receptor. These results suggest that the efpcan mediate estrogen actions such as cell growth in human breastcancer as a primary responsive gene.
Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer
Authors: Muungo Lungwani
Published: June 2020

The androgen receptor (AR) plays a critical role in the development and the progression of prostate cancer. Alterations in theexpression of AR coregulators lead to AR hypersensitivity, which is one of the mechanisms underlying the progression ofprostate cancer into a castrate-resistant state. Octamer transcription factor 1 (Oct1) is a ubiquitous member of the POUhomeodomainfamily that functions as a coregulator of AR. In our study, the contribution of Oct1 to prostate cancerdevelopment was examined. Immunocytochemistry analysis showed that Oct1 is expressed in the nuclei of LNCaP cells.siRNA-mediated silencing of Oct1 expression inhibited LNCaP cell proliferation. Immunohistochemical analysis of Oct1expression in tumor specimens obtained from 102 patients with prostate cancer showed a positive correlation of Oct1immunoreactivity with a high Gleason score and AR immunoreactivity (p 5 0.0042 and p < 0.0001, respectively). Moreover,patients with high immunoreactivity of Oct1 showed a low cancer-specific survival rate, and those patients with highimmunoreactivities of both Oct1 and AR exhibited poorer cancer-specific prognosis. Multivariate hazard analysis revealed asignificant correlation between high Oct1 immunoreactivity and poor cancer-specific survival (p 5 0.012). These resultsdemonstrate that Oct1 can be a prognostic factor in prostate cancer as a coregulator of AR and may lead to the developmentof a new therapeutic intervention for prostate cancer.
CDDO induces apoptosis via the intrinsic pathway in lymphoid cells.
Authors: Muungo Lungwani
Published: June 2020

The peroxisome-proliferator-activated receptor (PPAR) c agonist,CDDO, is under investigation for use in various malignancies.The mechanisms by which CDDO induces apoptosisare controversial. We have therefore sought to determine thesemechanisms using primary chronic lymphocyte leukemic (CLL)cells and Jurkat cell lines with defined apoptotic abnormalities.In these cells, CDDO induced-apoptosis involved caspaseindependentloss in mitochondrial membrane potential followedby caspase processing. The pattern of CDDO-inducedcaspase processing, defined by use of a caspase inhibitor,strongly suggested that caspase-9 was the apical caspase.Moreover, CDDO induced apoptosis in caspase-8 and FADDdeficientbut not in Bcl-xL overexpressing Jurkat cells. In CLLcells, CDDO induced an early release of mitochondrial cytochromec and Smac that preceded apoptosis. Thus, in both celltypes, CDDO induced apoptosis primarily by the intrinsicpathway with caspase-9 as the apical caspase. This hasimportant implications in the design of novel agents for thetreatment of CLL and other malignancies.
Safety, Acceptability and Adherence of Dapivirine Vaginal Ring in a Microbicide Clinical Trial Conducted in Multiple Countries in Sub-Saharan Africa
Authors: Muungo Lungwani
Published: June 2020

BackgroundThis was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containingvaginal ring as an HIV prevention technology for women.ObjectivesThe trial assessed and compared the safety, acceptability and adherence to product use ofa 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine,with a matching placebo ring among women from four countries in sub-Saharan Africa.Methods280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matchingplacebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated bypelvic examination, colposcopy, clinical laboratory assessments, and adverse events.Blood samples for determination of plasma concentrations of dapivirine were collected atWeeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring userswere determined post-trial. Participant acceptability and adherence to ring use wereassessed by self-reports.
Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity
Authors: Muungo Lungwani
Published: June 2020

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report thecharacterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, andnonimmunogenic PMLA [poly(b-L-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemictreatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties werecovalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directedagainst HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab(Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptorantibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the hostendothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth ofHER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neureceptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopydemonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemictreatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth andtumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab orAON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLAnanoplatform for combination cancer therapy.