bluuebunny/crossref_metadata_2025 huggingface dataset:
Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1
Authors: Yuan Xiangliang , Duan Yimin , Xiao Yi , Sun Kai , Qi Yutao , Zhang Yuan , Ahmed Zamal , Moiani Davide , Yao Jun , Li Hongzhong , Zhang Lin , Yuzhalin Arseniy E. , Li Ping , Zhang Chenyu , Badu-Nkansah Akosua , Saito Yohei , Liu Xianghua , Kuo Wen-Ling , Ying Haoqiang , Sun Shao-Cong , Chang Jenny C. , Tainer John A. , Yu Dihua
Published: April 2022

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies.

Significance:

The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies.

This article is highlighted in the In This Issue feature, p. 1599
Curcumin Attenuates Hydrocephalus via Activation of E2F Transcription Factor 4
Authors: Dong Ce , Yue Xiongfei , Zhu Lin , Ge Pengzhen , Zheng Guozhen , Ye Zhanying , Pan Baogen
Published: April 2022

Background: Recent studies have shown that curcumin can reduce the symptoms of hydrocephalus. However, the underlying mechanisms remain unclear. Our previous studies demonstrated that E2F transcription factor 4 (E2F4) protein plays an important role in hydrocephalus; hence, we hypothesized that E2F4 may involve in curcumin mediated anti-hydrocephalus benefits. Methods: E2F4 expression and functions in different human tissues and cell lines were determined and analyzed using the all RNA-seq and ChIP-seq sample and signature search database and ChIP-atlas database. Hydrocephalus mouse model was established through stereotactic injection of shE2F4 into frontal cortex. Mice were treated with curcumin, and then hydrocephalus severity, the expression of E2F4, and downstream targets were analyzed. Results: E2F4 was highly expressed in the nervous system, which was downregulated in the bran of hydrocephalus patients. Knockdown E2F4 in mice could mimic the phenotype of human hydrocephalus. Upon curcumin administration, E2F4 expression level was increased, and the hydrocephalus severity score was significantly decreased in mouse model. Mechanistically, curcumin attenuated hydrocephalus through activating E2F4 signaling pathway. Conclusion: Curcumin suppresses hydrocephalus progression via activation of E2F4, which could be a target for hydrocephalus treatment.
Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association
Authors: Duell P. Barton , Welty Francine K. , Miller Michael , Chait Alan , Hammond Gmerice , Ahmad Zahid , Cohen David E. , Horton Jay D. , Pressman Gregg S. , Toth Peter P. ,   on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Published: April 2022

Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is believed to affect >25% of adults worldwide. Unless specific testing is done to identify NAFLD, the condition is typically silent until advanced and potentially irreversible liver impairment occurs. For this reason, the majority of patients with NAFLD are unaware of having this serious condition. Hepatic complications from NAFLD include nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. In addition to these serious complications, NAFLD is a risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Accordingly, the purpose of this scientific statement is to review the underlying risk factors and pathophysiology of NAFLD, the associations with atherosclerotic cardiovascular disease, diagnostic and screening strategies, and potential interventions.
Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke
Authors: Endres Matthias , Moro Maria A. , Nolte Christian H. , Dames Claudia , Buckwalter Marion S. , Meisel Andreas
Published: April 2022

Inflammation and immune mechanisms are crucially involved in the pathophysiology of the development, acute damage cascades, and chronic course after ischemic stroke. Atherosclerosis is an inflammatory disease, and, in addition to classical risk factors, maladaptive immune mechanisms lead to an increased risk of stroke. Accordingly, individuals with signs of inflammation or corresponding biomarkers have an increased risk of stroke. Anti-inflammatory drugs, such as IL (interleukin)-1β blockers, methotrexate, or colchicine, represent attractive treatment strategies to prevent vascular events and stroke. Lately, the COVID-19 pandemic shows a clear association between SARS-CoV2 infections and increased risk of cerebrovascular events. Furthermore, mechanisms of both innate and adaptive immune systems influence cerebral damage cascades after ischemic stroke. Neutrophils, monocytes, and microglia, as well as T and B lymphocytes each play complex interdependent roles that synergize to remove dead tissue but also can cause bystander injury to intact brain cells and generate maladaptive chronic inflammation. Chronic systemic inflammation and comorbid infections may unfavorably influence both outcome after stroke and recurrence risk for further stroke. In addition, stroke triggers specific immune depression, which in turn can promote infections. Recent research is now increasingly addressing the question of the extent to which immune mechanisms may influence long-term outcome after stroke and, in particular, cause specific complications such as poststroke dementia or even poststroke depression.
The Contribution of the Structuring of the Canon to Debate about the Place of Wisdom in Biblical Theology
Authors: Goswell Gregory
Published: April 2022

Psalms, Job, Proverbs, Ecclesiastes and Song of Songs are routinely juxtaposed (in different orders and combinations) in the Hebrew and Greek OT canons. The implication of their propinquity is that the books were viewed by early readers as belonging together and mutually enriching. The regular collation of these five books means that they were treated as primary conversation partners, whose interaction took hermeneutical precedence over other possible intra-canonical links. Irrespective of whether it is decided that these generically diverse texts are to be designated a “wisdom collection,” contemporary readers of Scripture will benefit by taking into consideration that the books were placed together by ancient readers who viewed them as needing to be read in relation to each other.
The Ethics of Lament: Dereliction, Theodicy, Embodiment, and Discipleship
Authors: Ridlehoover Charles
Published: April 2022

One of the most important sets of texts for the church is the Passion narrative. A question of particular interest is the message behind Jesus’s words upon the cross: “My God, my God, why have you forsaken me?” By considering the shape and theology of Ps 22 as a lament, the reader becomes aware of the parallels between this psalm and Jesus’s crucifixion. These shared theological arcs give an intimate look into the death of Jesus and following his example. If disciples of Jesus are called to take up their crosses, the implication is that the theology of lament must be part of this embodied call. Thus, a proper understanding of the interaction of these two texts creates an ethic of lament resulting in a more holistic discipleship.
Psalm 115 and the Logic of Blessing
Authors: Chapman Stephen B.
Published: April 2022

Although not a well-known biblical psalm, Psalm 115 offers significant insights into the character of blessing in Second Temple piety. The psalm’s structure and catchword technique highlight a fundamental contrast between Israel’s God and the idols of the nations. The intangibility and apparent absence of Israel’s God are actually markers of this deity’s superiority and involvement in the world. God is present as the reliable recipient of human trust and ultimate source of human blessing. The human act of blessing is a means of “placing” one’s self and others within God’s good creation, and thus participating in God’s ongoing work of redemption. The act of blessing God affirms relationship with God.
How Is It Written? Mark 9:12, Heavenly Writ, and the King of the Jews Inscription
Authors: Schaser Nicholas J.
Published: April 2022

Scholars offer various scriptural precedents for how the Son of Man’s suffering is “written” according to Mark 9:12. This article proposes that Jesus’ suffering is written in heaven, and that it appears, ultimately, as the “King of the Jews” inscription (15:26). The use of γέγραπται in 9:12 does not preclude future application, so that Mark’s grammar allows for past writing to remerge during the Passion. The language that appears alongside the “King of the Jews” inscription in Mk 15:26–29 recalls earlier Markan references to Scripture, which imbues the title with authority on par with, but independent from, Israel’s Scriptures. Mark’s use of “King of the Jews” evokes Jesus’ prediction of maltreatment insofar as the phrase’s contexts either echo Mk 9:11–13 or draw on the Septuagint’s descriptions of suffering Judean kings. Thus, Mark’s inscription witnesses to the suffering written in heaven, and also explains why the Son of Man must suffer as King of the Jews.
Mission and Migration in the Formation of an Arab Middle Class
Authors: Phillips Julian Cole
Published: April 2022

Beginning in the late nineteenth century, there was significant migration of Arabs from the Ottoman Empire to the Americas, and such migrants often originated in the communities that had been subject to Protestant missionary programs. This article uses a micro-history of a single family to assess the relationship between missionary activity and emigration. The article concludes that Arabs deployed both involvement with missions (employment, conversion, and education) and temporary economic migration as strategies to join a transnational middle class.
Nation, Damned Nation and Statistics
Authors: Jammes Jérémy
Published: April 2022

The Summer Institute of Linguistics (SIL)’s main objective is to translate the Bible into all languages by collecting ethnolinguistic data thanks to the methods of participant-observation and lexical investigation. Tracing its origins to the mid-1930s in the United States and Central America, SIL started its missionary, linguistic and development activities in Southeast Asia in the 1950s, especially in the Philippines (1953) and Vietnam (1954). This article analyses the nature and trajectories of SIL members, investigating their missionary activities, their visual and statistical conception of conversion and ethnographic encounter, their conception of Pax Americana during the Vietnam war (1954–75). Both archive- and fieldwork-based investigation reveal what the SIL’s activity meant at the nexus of evangelism, linguistics, ethnography and US foreign policy, challenging some of the very simplified views of the operations of missionaries and religious NGO s in Southeast Asia during the Cold War.
Trends of Cancer Screenings, Diagnoses, and Mortalities During the COVID-19 Pandemic: Implications and Future Recommendations
Authors: Concepcion Jennifer , Yeager Matthew , Alfaro Sophie , Newsome Kevin , Ibrahim Joseph , Bilski Tracy , Elkbuli Adel
Published: April 2022

Introduction

The impact of the COVID-19 pandemic on cancer screenings and care has yet to be determined. This study aims to investigate the screening, diagnosis, and mortality rates of the top five leading causes of cancer mortality in the United States from 2019 to 2021 to determine the potential impact of the COVID-19 pandemic on cancer care.

Methods

A retrospective cohort study investigating the impact of the COVID-19 pandemic on screening, diagnoses, and mortality rates of the top five leading causes of cancer death (lung/bronchus, colon/rectum, pancreas, breast, and prostate), as determined by the National Institute of Health (NIH) utilizing The United States Healthcare Cost Institute and American Cancer Society databases from 2019 to 2021.

Results

Screenings decreased by 24.98% for colorectal cancer and 16.01% for breast cancer from 2019 to 2020. Compared to 2019, there was a .29% increase in lung/bronchus, 19.72% increase in colorectal, 1.46% increase in pancreatic, 2.89% increase in breast, and 144.50% increase in prostate cancer diagnoses in 2020 (all P < .01). There was an increase in the total number of deaths from colorectal, pancreatic, breast, and prostate cancers from 2019 to 2021.

Conclusion

There was a decrease in the screening rates for breast and colorectal cancer, along with an increase in the estimated incidence and mortality rate among the five leading causes of cancer deaths from 2019 to 2021. The findings suggest that the COVID-19 pandemic is associated with impaired cancer screening, diagnosis, and care, and further emphasizes the need for proactive screening and follow-up to prevent subsequent cancer morbidity and mortality.
Coming Full Circle: Reflections and Inspirations from a Cystic Fibrosis Patient Scientist Panel
Authors: Nowakowski Alexandra “Xan” C. H. , Balasa Gabriella “Ella” , Figueira Miriam F. , LaRosa Francis “Tré” J. , Lawlor James M. J.
Published: April 2022

Care for many progressive chronic diseases continues to improve, allowing patients to survive and thrive for longer periods of time1. People living with such conditions may now find themselves able to achieve long-term goals in education and career development2. Many people now occupy the dual roles of scientist and patient3. This commentary article synthesizes experiences of scientists and advocates with the progressive genetic disease cystic fibrosis (CF) who collaborated on a career development session for the Cystic Fibrosis Foundation’s inaugural ResearchCon event in 2019. It explores how such collaborations affirm and transform individual perspectives on patient science and its importance in broader scientific research agenda setting. We first share our own individual insights about the experience and impact of the ResearchCon panel session before progressing to discussion and future directions centering the shared insights from one another’s reflections.
Application and Evaluation of a Care Plan for Enhanced Recovery After Thyroidectomy
Authors: Zheng Lei , Zhang Shiyu
Published: April 2022

Purpose: To develop and evaluate a nursing care plan based on the ERAS (Enhanced Recovery After Surgery) approach for thyroid surgery patients. Methods: A nursing care plan has been developed after the literature review and focus group discussion. The content was validated using the Delphi method. Then, a quasi-experimental study was designed. A total of 120 cases with thyroid surgery at Ruijin Hospital from March to June 2018 were divided equally into an ERAS group and a conventional group Results: The nursing care plan consisted of 13 first-level and 32 second-level indicators. ( P < .001). Strikingly the outcomes, such as pain scores, length of hospital stay, and hospitalization costs, were significantly less in the ERAS group than those in the conventional group (P<.001), while no difference was detected in the postoperative complications rate. Conclusion: A scientific and reliable nursing care plan has been used for thyroidectomy patients to enhance recovery.
Management Strategies of Fibrous Dysplasia Involving the Paranasal Sinus and the Adjacent Skull Base
Authors: Shi Li-li , Xiong Peng , Zhen Hong-tao
Published: April 2022

Objective

Current management of fibrous dysplasia (FD) involving the paranasal sinuses and the adjacent skull base is currently controversial. This study aims to present our experience in the management strategy of FD that involves the paranasal sinuses and the adjacent skull base.

Methods

Twenty three patients from 2006 to 2019 with monostotic fibrous dysplasia (MFD), polyostotic fibrous dysplasia (PFD), or McCune-Albright syndrome (MAS) involving the paranasal sinuses and the adjacent skull base were retrospectively reviewed. This study series was divided into 3 groups based on management strategies: the observation group, the surgery group, and the optic nerve decompression group.

Results

The observation group included 9 patients with asymptomatic MFD with stable condition during the follow-up period of 15 to 164 months. The surgery group included 10 symptomatic patients with MFD who had personalized endoscopic endonasal surgery. The symptoms of the patients were relieved after surgery. The optic nerve decompression group included 4 patients with visual loss, who underwent endonasal endoscopic optic nerve decompression (EOND) with the aid of image-guided navigation. Their vision improved after surgery.

Conclusions

Clinical observation and periodic computed tomography (CT) scan are adopted for asymptomatic patients. Surgery is indicated in symptomatic patients. Optic nerve decompression is recommended as soon as possible if the patient has visual loss, whereas prophylactic decompression is not recommended if the optic nerve is encroached by FD without visual loss. Navigation plays an important role in endoscopic surgery involving the paranasal sinuses and the adjacent skull base, especially in FD resection and optic nerve decompression.
Synovial Fluid Cytokine Profile at the Time of Arthroscopy Explains Intermediate-Term Functional Outcomes
Authors: Kingery Matthew T. , Adams Anngela C. , Manjunath Amit K. , Berlinberg Elyse J. , Markus Danielle H. , Strauss Eric J.
Published: April 2022

Background:

The intra-articular immune response after ligamentous, meniscal, or focal chondral knee injuries likely plays a role in intra-articular healing and the onset and progression of posttraumatic osteoarthritis.

Purpose:

To evaluate the association of synovial fluid cytokine concentrations measured at the time of knee arthroscopy with intermediate-term functional outcomes after knee arthroscopy based on the Lysholm score.

Study Design:

Cohort study; Level of evidence, 2.

Methods:

This was a prospective cohort study of patients undergoing arthroscopic knee surgery. Synovial fluid was aspirated from the injured knee immediately before surgical incision, and the concentrations of 10 cytokines were analyzed using immunoassay. Principal component regression was used to create a model to predict patient-reported Lysholm score at a minimum of 5 years postoperatively. Hierarchical clustering was performed to identify groups of patients with similar synovial fluid inflammatory phenotypes. Lysholm scores and cytokine concentrations were compared between clusters.

Results:

A total of 26 patients (mean age, 40.33 ± 16.40 years) were included in the analysis. The mean duration between surgery and follow-up was 6.69 ± 0.72 years. A model consisting of 2 principal components (PC1, PC2) explained 62.48% of the variance in the cytokine data and 52.03% of the variance in intermediate-term Lysholm score. Hierarchical clustering resulted in 3 patient clusters based on the principal components used in the regression model. Despite no baseline differences in Lysholm score, cluster 3 demonstrated significantly greater intermediate-term Lysholm score compared with cluster 2 (94.33 vs 76.09, respectively; 95% CI, 5.96-30.52; P = .006) and cluster 1 (94.33 vs 52.33, respectively; 95% CI, 24.09-59.91; P = .003). Cluster 3, when compared with the overall means, was characterized by greater PC1 value (1.01 vs 0.00, respectively; P = .030) and greater PC2 value (0.86 vs 0.00, respectively; P = .002).

Conclusion:

The concentrations of select synovial fluid cytokines assessed at the time of knee arthroscopy can be used to explain more than half of the variance in intermediate-term functional outcomes.
A Rapid Phenotypic Assay for Detecting Multiple Nucleoside Analogue Reverse Transcriptase Inhibitor-Resistant HIV-1 in Plasma
Authors: Qari Shoukat H , Winters Mark , Vandamme Anne-Mieke , Merigan Thomas , Heneine Walid
Published: April 2022

Zidovudine and other nucleoside analogue reverse transcriptase inhibitors (NRTIs), like zalcitabine and didanosine used for treatment of individuals infected with HIV-1, can select for viruses with Q151M and other associated mutations (for example, A62V, S68G, V75I, F77L, F116Y) in the reverse transcriptase (RT) enzyme. These mutations confer resistance to multiple nucleoside analogues, and thereby compromise the efficacy of this class of drugs. Presently available phenotypic assays for detection of multiple nucleoside analogue resistant (MNR) HIV-1 require testing for each NRTI individually. Here we report an enzymatic RT assay that uses resistance to zidovudine triphosphate (zidovudine-TP) as a diagnostic biochemical marker of MNR HIV-1. This assay exploits the different biochemical mechanisms for zidovudine-resistance conferred by either Q151M or T215Y/F mutations and the inability of conventional RT assays to detect T215Y/F-associated zidovudine resistance. The assay detects RT activity directly in plasma by using Amp-RT, an ultra-sensitive PCR-based RT assay. We show that enzymatic resistance to zidovudine-TP is specific to MNR RT and is distinguishable from both wild-type (WT) and RT containing classical zidovudine-resistant mutations (D67N, K70R, T215Y/F, K219Q). Compared to WT, MNR HIV-1 RT had 5- to 36-fold increases in the concentration of drug required to inhibit 50% (IC50) of RT activity, depending on the presence of Q151M alone or with additional MNR mutations. A screening assay utilizing 1 μM zidovudine-TP was developed and validated on 14 reference isolates, 37 plasma specimens, and seven patient-derived viruses. Twenty-three specimens were found to have reduced susceptibility to zidovudine-TP, and all had Q151M. In contrast, 21 specimens were sensitive to zidovudine-TP, of which 12 had WT genotypes, four had T215Y/F, and five had T69S-insertions along with T215Y/F mutations. This RT-based phenotypic assay provides a specific and rapid tool for the direct identification and monitoring of Q151M-associated MNR HIV-1 in plasma.
Drug Resistance Mutations during Structured Treatment Interruptions
Authors: Yerly Sabine , Fagard Catherine , Günthard Huldrych F , Hirschel Bernard , Perrin Luc ,   the Swiss HIV Cohort Study (SHCS)
Published: April 2022

Background

We assessed whether treatment interruptions induce selection of mutations associated with drug resistance in the Swiss–Spanish Intermittent Treatment Trial (SSITT). Patients had been on HAART without previous failure and had undetectable viraemia for at least 6 months. Their HAART was interrupted for 2 weeks and restarted for 8 weeks. After four of these cycles, treatment was definitively interrupted at week 40.

Methods

Genotypic resistance testing was performed in 87/97 Swiss patients: in those failing treatment before week 40, at the time of first viral rebound >500 copies/ml off treatment and preceding failure to reach RNA <50 copies/ml after 8 weeks of re-treatment; for patients without virological failure, on the first sample with HIV-1 RNA >1000 copies/ml after week 40.

Results

Mutations associated with drug resistance were detected in 9/25 (36%) patients with virological failure during the first 40 weeks and in 6/59 (10%) patients after week 40. Overall, drug resistance mutations were detected in 17% of patients, all but two with the 184V/I mutation. Among the 74 patients receiving lamivudine, the M184V/I mutation was detected in 13/74 (17.6%) patients. A wild-type codon at position 184 was detected in previous samples in all b'ut two. The relative risk for virological failure was 2.55-fold higher in patients with the M184V/I mutation than in patients without detectable mutation ( P=0.007).

Conclusions

The M184V/I mutation is frequently selected during repeated treatment interruptions.
Intracellular Accumulation of Nelfinavir and Its Relationship to P-Glycoprotein Expression and Function in HIV-Infected Patients
Authors: Hennessy Martina , Clarke Susan , Spiers J Paul , Kelleher Dermot , Mulcahy Fiona , Hoggard Patrick , Back David , Barry Michael
Published: April 2022

Objective

To compare plasma and intracellular nelfinavir pharmacokinetics, and determine their relationship to P-glycoprotein (P-gp) expression and function in lymphocytes of HIV-infected patients.

Methods

A pharmacokinetic study of 12 patients receiving nelfinavir plus dual nucleoside analogue therapy. Blood samples were taken at intervals to 12 h. Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation, and nelfinavir extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular nelfinavir samples were assayed by high performance liquid chromatography linked to mass spectrometry. P-gp expression and function were measured by flow cytometric analysis. Data were analysed by non-compartmental analysis using WinNonLin pharmacokinetic software.

Results

The mean intracellular nelfinavir AUC0–12 (mean ±SE) was about ninefold higher than that of plasma (264 200 ±63420 vs 29250 ±6629 ng/ml/h; P<0.001, and intracellular Cmin and C0 values for nelfinavir were five- to sixfold higher than that of plasma (Cmin: 5712 ±2156 vs 1062 ±357 ng/ml; C0: 15860 ±3662 vs 2553 ±539 ng/ml; P<0.0005). The intracellular nelfinavir Cmax was 15-fold higher than plasma (59420 ±13940 vs 3986 ±822 ng/ml; P<0.0005). There were no differences between plasma and intracellular values for Tmax, elimination half-life or mean residence time. In patients chronically treated with nelfinavir mean P-gp expression was 8.85 ±1.3 MFI, there was no correlation between Pgp expression and either intracellular AUC0–12 (r=–0.35; P=0.29) or intracellular C0 values. There was a correlation between intracellular nelfinavir concentrations and P-gp function at baseline (r=0.59; P<0.05). Basal P-gp-mediated rhodamine efflux was 61.0 ±4.2%. In the presence of ritonavir, cellular rhodamine efflux decreased to 25.6 ±5.5% ( P=0.001), representing an additional reversible efflux potential of 56.1 ±9.78%. There was a strong correlation between plasma and intracellular AUC0–12 for nelfinavir (r=0.75; P=0.011).

Conclusions

Nelfinavir undergoes significant intracellular accumulation within the PBMCs of HIV-infected patients, which may be in part related to its moderate ability to inhibit P-gp-mediated drug efflux. The addition of ritonavir further reduced P-gp function. Intracellular accumulation of nelfinavir correlated with P-gp function but not P-gp expression, suggesting pump activity is substrate concentration-dependant. There was a significant correlation between plasma and intracellular nelfinavir concentrations, suggesting one is a good surrogate marker of the other.
Estimates of Intracellular Delay and Average Drug Efficacy from Viral Load Data of HIV-Infected Individuals under Antiretroviral Therapy
Authors: Dixit Narendra M , Markowitz Martin , Ho David D , Perelson Alan S
Published: April 2022

We analyse viral load data of five patients under ritonavir monotherapy using a model of HIV dynamics under antiretroviral therapy that includes both drug pharmacokinetics and the intracellular delay from the time of cell infection to viral production. Using this approach we separate pharamacokinetic from intracellular delays, and obtain new estimates of intracellular delay and the antiviral efficacy of ritonavir. We find the average intracellular delay to be 1 day, in agreement with experiments. The average viral generation time is now estimated at 2 days, resulting in ∼180 replication cycles per year. The model also reveals that ritonavir monotherapy is ∼65% as efficacious as a recently used potent four-drug therapy, suggesting that selection for drug resistance may be facilitated by the relatively low efficacy of individual drugs, contributing in part to the inherent limitations of current therapies in combating HIV-1 infection.
Discordant Conclusions from HIV Clinical Trials — An Evaluation of Efficacy Endpoints
Authors: Hill Andrew , DeMasi Ralph
Published: April 2022

The three main components of long-term efficacy for a combination of antiretrovirals are: (i) the strength of the antiviral effect, (ii) toxicity profile and (iii) patient acceptability of the regimen. Intent-to-treat (ITT) analysis, where discontinuations and switches are considered failures [ITT, switch equals failure (ITT/S=F)], is a regulatory standard for analysing the efficacy of anti-retrovirals. A review of all clinical trials published in FDA product labels was conducted, including all clinical trials of boosted protease inhibitor- or nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in treatment-naive patients, and all clinical trials of antiretrovirals in treatment-experienced patients. Clinical trials where the results are presented in the standard ITT/S=F method were included. For randomized clinical trials in treatment-naive patients, the majority of treatment discontinuations have been either for toxicity (32%) or patient refusal of treatment (41%), with only 27% of failure endpoints for virological reasons among recent clinical trials in naive patients. Therefore, there is the potential for the results from ITT/S=F analysis to be driven by non-virological endpoints – a new treatment can be classified as ‘more efficacious’ than control owing to fewer discontinuations due to adverse events or patient preference.

In order to understand the intrinsic potency of the anti-retroviral regimen under study, ITT analysis needs to be supplemented by standardized as-treated analyses, excluding withdrawals for toxicity or other reasons. To evaluate the efficacy of a treatment strategy or sequential treatment regimens, the ‘ITT, switch included’ (ITT/SI) method: where changes from the initial randomized treatment are not classified as treatment failure – can be used. However, interpretation of clinical trials using ITT/SI analysis is difficult and depends on the frequency of treatment switching in the different arms of a trial.

Conclusions on efficacy from clinical trials can depend on the primary analysis used; most commonly, treatments could be significantly different by ITT/S=F analysis, but then interpreted as equivalent using the ITT/SI or as-treated methods.
Visceral Leishmaniasis during Pegylated Interferon Therapy for Chronic Hepatitis C: First Report
Authors: Cascio Antonio , Antinori Spinello , Ricciardi Filippo , Costantino Giuseppa , Iaria Chiara
Published: April 2022

See: Puoti et al. Use of pegylated interferons is associated with an increased incidence of infections during combination treatment of chronic hepatitis C: a side effect of pegylation? Antiviral Therapy 2004; 9:627–630.
In Vivo Effects of Highly Active Antiretroviral Therapies Containing the Protease Inhibitor Nelfinavir on Mitochondrially Driven Apoptosis
Authors: Miró Òscar , Villarroya Joan , Garrabou Glòria , López Sònia , de la Concepción Marisa Rodríguez , Pedrol Enric , Martínez Esteban , Giralt Marta , Gatell Josep M , Cardellach Francesc , Casademont Jordi , Villarroya Francesc
Published: April 2022

Background

In vitro studies have reported controversial effects of protease inhibitors (PIs) on mitochondrially driven apoptosis. Additionally, since PIs in the clinical setting are almost always given in combination with nucleoside analogues, which may have negative effects on mitochondrial DNA (mtDNA), the impact of PI-containing highly active antiretroviral therapy (HAART) on apoptosis and mtDNA content is unclear.

Patients and methods

A cross-sectional study was performed including 20 HIV-negative (HIV-) patients, 16 HIV-positive, antiretroviral-naive (HIV+) patients and 17 HIV-positive patients receiving the PI nelfinavir (NFV) plus zidovudine and lamivudine (AZT+3TC) or didanosine and stavudine (ddI+d4T) - collectively known as HIV+PI - as first-line antiretroviral treatment for at least 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated. BCL2 expression (anti-apoptotic) and the levels of the cleaved, active form of caspase-9 (pro-apoptotic) were determined by western blot. An index of mitochondrially driven apoptotic activation was estimated calculating the ratio caspase-9:BCL2. Mitochondrial DNA content was measured by real-time PCR.

Results

BCL2 expression was lower in HIV+ than in HIV-patients ( P<0.01), whereas levels of caspase-9 were higher ( P=0.001). The caspase-9:BCL2 ratio was significantly increased in HIV+ compared with HIV- individuals ( P<0.001). Mitochondrial DNA content was also decreased in HIV+ compared with HIV- patients ( P<0.001). The HIV+PI group exhibited a trend to normalization for BCL2 expression and caspase-9 compared with the HIV+ group, whereas the caspase-9:BCL2 ratio significantly improved (decreased, P<0.05 compared with HIV+ group). The mtDNA content in the HIV+PI group was similar to that of the HIV+ group, although the results of mtDNA content differed depending on whether NFV was combined with AZT+3TC (preserved) or with ddI+d4T (depleted). Conversely, no differences were found in apoptotic markers between the two subgroups of HIV+PI.

Conclusions

NFV-based PI-containing HAART regimens may exert some beneficial effects counteracting the increased mitochondrially driven apoptosis present in HIV-infected people.
A Multiphase Model of the Dynamics of HBV Infection in Hbeag-Negative Patients during Pegylated Interferon-α2A, Lamivudine and Combination Therapy
Authors: Colombatto Piero , Civitano Luigi , Bizzarri Ranieri , Oliveri Filippo , Choudhury Somesh , Gieschke Ronald , Bonino Ferruccio , Brunetto Maurizia R ,   Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group, Farci P , Germanidis G , Kittis G , Cadeo G , Pastore G , Hadziyannis S
Published: April 2022

Using a multiphase bio-mathematical model, we studied the dynamics of hepatitis B virus (HBV) infection in 72 HBeAg-negative patients who received 48 weeks of either lamivudine (3TC; 25 patients); pegylated interferon-α2a (peg-IFN-α2a) 180 mg weekly plus 3TC (23 patients), or peg-IFN-α2a 180 mg weekly plus placebo (24 patients).

During the first month of therapy most of the 3TC -/+ peg-IFN-α2a treated patients showed a multiphase decay of viral load: during the first two phases, where we hypothesized a direct inhibition of virus production, the mean viral production per infected cell was reduced by 2.22 log10 and 2.36 log10, respectively. At variance, peg-IFN-α2a treated patients had a biphasic profile: the first phase HBV DNA decline was slower than that observed in 3TC patients (mean HBV DNA t1/2=1.6 ±1.1 days and 9.5 ±3.0 h, respectively) and the direct antiviral effect reduced virus production by 1.14 log10 From day 14 onwards (third or second phase according to multi- or biphasic patterns), HBV DNA declined mainly because of the infected hepatocyte clearance that slowed down in approximately 50% of the patients from day 35, possibly because of a negative feedback on the immune system activity. Computing the number of infected cells at the end of therapy we found that peg-IFN-α2a and 3TC monotherapy determined a similar reduction of infected hepatocytes (mean: -3.3 log10), whereas there was a greater reduction in combination therapy patients (-5.0 versus -3.3 log10, P=0.039). In conclusion, peg-IFN-α2a, in spite of having direct antiviral activity lower than that of 3TC, achieved a comparable reduction of infected hepatocytes, possibly because of a higher infected cell clearance rate.
HIV-1 Drug-Resistance Mutations among Newly Diagnosed Patients before Scaling-Up Programmes in Burkina Faso and Cameroon
Authors: Vergne Laurence , Diagbouga Serge , Kouanfack Charles , Aghokeng Avelin , Butel Christelle , Laurent Christian , Noumssi Nathalie , Tardy Michèle , Sawadogo Adrien , Drabo Joseph , Hien Hervé , Zekeng Léopold , Delaporte Eric , Peeters Martine
Published: April 2022

We analysed whether mutations associated with resistance to antiretroviral (ARV) drugs circulate among treatment-naive HIV-1-infected individuals at a period when these drugs started to become more widely available in Africa. Overall, major resistance mutations in the pol gene, as defined by the International AIDS Society Resistance Testing-USA panel, were observed in 16 treatment-naive individuals. Eight of the 97 patients tested in Burkina Faso bore mutations conferring resistance to one drug class of ARV drugs: two to nucleoside reverse transcriptase inhibitors (NRTIs; M41L [ n=1], M41L+T69S [ n=1]), four to non-NRTIs (NNRTIs; V106A/V [ n=1] and V108I [ n=3]) and two to protease inhibitors (PIs; L33F [ n=2]). In Cameroon, resistance mutations were identified in 8 of 102 patients: three to PIs (M46I/L [ n=2], L33F [ n=1]), three to NRTIs (T69N/T [ n=1], M184V [ n=1], A62V [ n=1]) and two to NNRTIs (P236L [ n=1], V108I [ n=1]). It is important to note that not all geno-typic drug-resistance algorithms give similar interpretations to the observed mutations. Population surveillance for ARV drug resistance is required and should be included in all implementation programmes.
Lamivudine and Indinavir/Ritonavir Maintenance Therapy in Highly Pretreated HIV-Infected Patients (Vista Anrs 109)
Authors:   for the ANRS 109 VISTA Study Group, Launay Odile , Duval Xavier , Dalban Cécile , Descamps Diane , Peytavin Gilles , Certain Agnès , Mouajjah Saïd , Ralaimazava Pascal , Verdon Renaud , Costagliola Dominique , Clavel François
Published: April 2022

Objective

In patients with extensive HIV resistance, one option is to delay salvage therapy until new drugs become available. We hypothesized that this delay period could be based on a simplified treatment, which would reduce drug toxicity, stabilize resistance, and prevent resurgence of wild-type virus.

Methods

A prospective 24-week treatment simplification study in HIV-1-infected patients having failed several lines of antiretroviral therapy, with CD4+ T-cell counts ≥100 cells/ml, plasma HIV RNA (viral load [VL]) ≥4 log10 copies/ml and a resistance genotype predicting less than two active drugs. Treatment associated ritonavir-boosted low-dose indinavir (200 mg twice daily) and lamivudine (150 mg twice daily). The primary endpoint was a decrease in CD4+ T-cell counts ≥25% or increase in VL ≥0.7 log copies/ml relative to baseline.

Results;

Twenty-six patients were included. Baseline median VL was 4.5 log10 copies/ml and median CD4+ T-cell count was 290 cells/ml. During the study, 10/26 patients (38%, 95% confidence interval=20.2–59.4) reached the primary endpoint. No patient had an AIDS-defining event. At week 24, the median change in plasma VL was +0.2 log10 copies/ml (interquartile range (IQR): 0–0.5; P=0.003). The median change in CD4+ T-cell counts was -49 cells/ml (IQR: -14 to -93, P<0.001), with a median decline slope of 10 cells/ml/month, which was not different from that measured under full highly active antiretroviral therapy during the 6 months preceding inclusion. There were no significant changes in HIV-1 protease and reverse transcriptase genotypes during the study.

Conclusions

In patients with advanced resistance, treatment simplification prevented resurgence of wild-type HIV, reduced drug burden, but failed to stabilize progression of the immune deficiency.
HIV-1 Transmission Cluster with M41L ‘Singleton’ Mutation and Decreased Transmission of Resistance in Newly Diagnosed Swedish Homosexual Men
Authors: Lindström Anna , Ohlis Anna , Huigen Marleen , Nijhuis Monique , Berglund Torsten , Bratt Göran , Sandström Eric , Albert Jan
Published: April 2022

Objective

To investigate the prevalence of HIV-1 with major drug resistance-associated mutations among 261 men who have sex with men (MSM) who were newly diagnosed as HIV-1-infected at Venhälsan, Stockholm, between 1992–2002.

Methods

Major resistance-associated mutations were identified using an in-house method on stored plasma samples collected within 6 months of diagnosis. Additional samples were investigated from selected patients. Phylogenetic tree analyses were used to study evolutionary relationships between the viruses. Epidemiological data were retrieved from the partner notification investigations and the medical records.

Results

Informed consent as well as results from the resistance test were available for 201 out of 261 patients (77%) diagnosed during 1992–2002. Viruses from 28 of these 201 patients (14%) displayed major resistance-associated mutations; 27 of these viruses displayed only zidovudine/stavudine resistance-associated mutations. None of the patients displayed resistance mutations to protease inhibitors. The prevalence of resistance-associated mutations decreased over time; 20% in 1992–1996 versus 9% in 1997–2002 ( P=0.04). A transmission cluster involving six patients with a singleton M41L mutation was identified. These viruses were phenotypically sensitive to zidovudine and stavudine. The M41L mutation, as well as most other resistance mutations, was stable for many years after transmission and may have been fixated by other putative compensatory mutations.

Conclusions

In this Swedish population of MSM with newly diagnosed HIV-1 infection, the prevalence of resistance-associated mutations decreased over time. Reversion of resistance-associated mutations following transmission was slow and incomplete. A large transmission cluster with an interesting M41L singleton mutation was also observed.
Comparison of Mass Spectrometric Analysis and TRUGENE™ HBV Genotyping for Monitoring Lamivudine Resistance in Chronic Hepatitis B Patients
Authors: Woo Hee-Yeon , Park Hyosoon , Kim Byung-Ik , Jeon Woo-Kyu , Cho Yong Kyun , Kim Young Jae
Published: April 2022

Background

There is an increasing need for the early detection of emerging mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of hepatitis B virus (HBV) DNA polymerase with using sensitive molecular methods.

Methods

We evaluated the usefulness of monitoring lamivudine resistance using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-based assay (the restriction fragment mass polymorphism; RFMP) in comparison with the direct sequencing assay, the TRUGENE™ HBV genotyping kit. We also investigated the treatment responses in relation to the presence of YMDD mutants. The sera from 50 chronic HBVs patients were analysed for the presence of YMDD mutants by performing RFMP and TRUGENE. The results at codons 180 and 204 were compared for 46 patients.

Results

The concordance rate between the two assays was 65.2% (30/46). All the discordance corresponded to the detection of additional virus populations by RFMP. Early detection of mutants before viral breakthrough was accomplished by RFMP in two patients. Persistence of very low viraemia was observed in five patients who harboured mutant virus populations. Additional information was provided by TRUGENE in eight patients.

Conclusions

RFMP showed a superior ability for detecting minor mutant virus populations compared with TRUGENE. However, the results of highly sensitive RFMP should be interpreted carefully because lamivudine could be effective despite the presence of mutants. RFMP could be a practical tool in conjuction with regular measurements of the HBV viral load for the early detection of lamivudine resistance and the timely introduction of new antiviral drugs.
Improvements in Parameters of End-Stage Liver Disease in Patients with HIV/HBV-related Cirrhosis Treated with Tenofovir
Authors: Matthews Gail V , Cooper David A , Dore Gregory J
Published: April 2022

Background

Mortality related to end-stage liver disease is increasing in HIV/hepatitis B virus (HBV)-coinfected patients and effective treatment options are limited. Tenofovir is now widely used in HIV/HBV coinfection and results in significant HBV suppression, in both patients with and patients without lamivudine resistance. The safety and efficacy of tenofovir in HIV/HBV cirrhosis has not been previously described.

Methods

Seven cirrhotic HIV/HBV patients treated with tenofovir were identified within the HIV clinic. Parameters of hepatic function, CD4+ T-cell counts, HBV DNA levels and Child-Pugh Class (C-P-C) were determined before and after addition of tenofovir. All patients had prior lamivudine experience with a median baseline HBV DNA of 6.23x107 copies/ml.

Results

Four of seven patients were C-P-C -A and hepatitis ‘e’ antigen (HBeAG) was positive in 4/7 patients. After a median duration of tenofovir of 28 months, all laboratory parameters improved, with significant changes in albumin and prothrombin (PT) (median pre-/post-tenofovir: alanine aminotransferase 63/39; bilirubin 26/18; albumin 39/44, P=0.028; PT 17.5/15, P=0.018). All three patients with C-P-C -B or -C improved to C-P-C -A, which for one patient enabled removal from the liver transplant waiting list. Three patients lost HBeAG with two anti-HBe seroconversions. Median HBV DNA was suppressed to <35 copies/ml.

Conclusions

This study demonstrates that tenofovir can produce HBV viral suppression, HBeAg seroconversion and improvement in markers of hepatic function in HIV/HBV-coinfected patients with cirrhosis. The potential reversal of end-stage liver disease may provide an important survival benefit in this population.
Relationship of Mitochondrial DNA Depletion and Respiratory Chain Activity in Preadipocytes treated with Nucleoside Reverse Transcriptase Inhibitors
Authors: Stankov Metodi V , Lücke Thomas , Das Anibh M , Schmidt Reinhold E , Behrens Georg MN
Published: April 2022

Objective

To study the impact of adipocyte differentiation on nucleoside reverse transcriptase inhibitor (NRTI)-mediated mitochondrial DNA (mtDNA) depletion and to correlate mtDNA depletion with the activity of the respiratory chain complexes.

Methods

We studied adipocyte phenotype, viability, differentiation (CCAAT/enhancer-binding protein [C/EBP]-α and peroxisome proliferator-activated receptor [PPAR]-γ expression), adiponectin production, mtDNA content, activity of respiratory chain complexes and citrate synthase activity in 3T3–L1 adipocytes. Cells were exposed to zidovudine (6 μM or 180 μM), stavudine (3 μM or 90 μM), and zalcitabine (0.1 μM or 3 μM) at different developmental stages for up to 2 months.

Results

Zidovudine and stavudine impaired adiponectin production in vitro at therapeutic Cmax concentrations, but none of the tested NRTIs had a negative impact on adipocyte differentiation or led to mtDNA depletion at these concentrations. Susceptibility of preadipocytes to mtDNA depletion was dependent on cell proliferation and differentiation, and mtDNA depletion occurred only after exposure to high drug concentrations. Under these conditions, stavudine led to up to 80% mtDNA depletion in both dividing and differentiating preadipocytes, whereas zidovudine affected mtDNA only in the differentiating cells. Despite mtDNA depletion by NRTIs, activity of the respiratory chain complexes was found to be unimpaired.

Conclusions

We found mtDNA depletion in adipocytes but proliferation and/or differentiation of the cells seems to be a prerequisite for this phenomenon. Depletion of mtDNA up to 80%, however, was not associated with impaired respiratory chain activity in 3T3-L1 preadipocytes.