Network targeting combination therapy of synthetic lethal vulnerabilities in 9p21-deficient glioblastoma: A case report.

Background: Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case report describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21. Methods and Results: Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes. Conclusion: Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.

Network-targeting combination therapy of leptomeningeal glioblastoma using multiple synthetic lethal strategies: a case report.

Network targeting of disease-specific nodes represents a useful principle for designing combination cancer therapy. In this case of a patient with relapsed leptomeningeal glioblastoma, comprehensive molecular diagnosis led to the identification of a disease network characterized by multiple disease-specific synthetic lethal vulnerabilities involving DNA repair, REDOX homeostasis, and impaired autophagy which suggested a novel network-targeting combination therapy (NTCT). A treatment regimen consisting of lomustine, olaparib, digoxin, metformin, and high dose intravenous ascorbate was employed using the principle of intra-patient dose escalation to deliver the treatment with adequate safety measures to achieve a definitive clinical result.

Health Care Provider Decisions to Initiate Oral HIV Preexposure Prophylaxis in New York City Public Sexual Health Clinics.

BACKGROUND: Oral HIV preexposure prophylaxis (PrEP) is safe and effective but underutilized. Health care providers' beliefs about PrEP and attitudes toward people who could benefit may affect PrEP access. METHODS: This mixed-methods study (2016-2018) was conducted in 8 New York City public sexual health clinics that implemented a PrEP program. Data included 32 in-depth qualitative interviews with clinicians, quantitatively coded to reflect their PrEP beliefs; a provider questionnaire; and 6 months of medical record visit data for these providers. Among patients with a PrEP indication, we examined the odds of a patient being initiated on PrEP associated with providers' PrEP beliefs and demographic characteristics, and patient characteristics. RESULTS: Providers reported strong support for offering PrEP to eligible patients. The majority denied concerns about possible development of drug-resistant viral strains, giving PrEP to people who might not benefit, and PrEP toxicity. Nevertheless, about one-third agreed with each of these concerns, and 55% thought PrEP use might limit condom use. Of 2176 patients with a PrEP indication, 20% were initiated. Providers with more restrictive PrEP beliefs did not have lower odds of initiating patients on PrEP. Women as well as Black and Latinx patients were less likely to be initiated on PrEP. CONCLUSIONS: Contrary to our hypotheses, providers' negative PrEP beliefs did not seem to reduce initiation of PrEP for eligible patients. This may be attributable to clear clinical protocols, strong staff support, and training on implementing PrEP in this setting. Racial and gender disparities in PrEP uptake urgently require attention.

Data on the techno-economic and financial analyses of hybrid renewable energy systems in 634 Philippine off-grid islands.

This data article contains the location, energy consumption, renewable energy potential, techno-economics, and profitability of hybrid renewable energy systems (HRES) in 634 Philippine off-grid islands. The HRES under consideration consists of solar photovoltaics, wind turbines, lithium-ion batteries, and diesel generators. The islands were identified from Google Maps™, Bing Maps™, and the study of Meschede and Ocon et al. (2019) [1]. The peak loads of these islands were acquired from National Power Corporation - Small Power Utilities Group (NPC-SPUG), if available, or estimated from the island population otherwise. Hourly-resolution load profiles were synthesized using the normalized profiles reported by Bertheau and Blechinger (2018) [2]. Existing diesel generators in the islands were compiled from reports by NPC-SPUG, while monthly average global horizontal irradiance and wind speeds were taken from the Phil-LIDAR 2 database. Islands that are electrically interconnected were lumped into one microgrid, so the 634 islands were grouped into 616 microgrids. The HRES were optimized using Island System LCOEmin Algorithm (ISLA), our in-house energy systems modeling tool, which sized the energy components to minimize the net present cost. The component sizes and corresponding techno-economic metrics of the optimized HRES in each microgrid are included in the dataset. In addition, the net present value, internal rate of return, payback period, and subsidy requirements of the microgrid are reported at five different electricity rates. This data is valuable for researchers, policymakers, and stakeholders who are working to provide sustainable energy access to off-grid communities. A comprehensive analysis of the data can be found in our article "Techno-economic and Financial Analyses of Hybrid Renewable Energy System Microgrids in 634 Philippine Off-grid Islands: Policy Implications on Public Subsidies and Private Investments" [3].

Durable Viral Suppression Among People with HIV and Problem Substance Use in the Era of Universal Antiretroviral Treatment.

This study explored factors associated with durable viral suppression (DVS) among two groups of people living with HIV (PLWH) and problem substance use in the context of universal antiretroviral treatment initiation. Participants (N = 99) were recruited between 2014-2017 from public sexual health clinics [SHC] and a hospital detoxification unit [detox]). DVS (NYC HIV surveillance registry) was defined as two consecutive viral load tests ≤ 200 copies/mL, ≤ 90 days apart, with all other viral loads suppressed over 12 or 18 months. Detox participants were significantly older, with more unstable housing/employment, substance use severity, and longer-term HIV vs. SHC participants. Older age, opioid and stimulant use disorder were significantly associated with lower odds of DVS, while fulltime employment and stable housing were significantly associated with higher odds of DVS at 12-month follow-up. Patterns held at 18-month follow-up. Co-located substance use and HIV services, funding for supportive housing, and collaborative patient-provider relationships could improve DVS among populations with the syndemic of problem substance use, poverty, and long-term HIV.

Lipase immobilization on biodegradable film with sericin.

An ecofriendly and low-cost film composed by cassava starch, polyvinyl alcohol, and sericin blend (CS-PVA-SS) was synthesized, characterized, and applied as a novel support for Botryosphaeria ribis EC-01 lipase immobilization by enzyme-film-enzyme adsorption. Film revealed thickness between 230 and 309 µm and higher flexibility and malleability in comparison with film without SS. Based on p-nitrophenyl palmitate hydrolysis reaction, the activity retention of immobilized lipase was 987%. For optimal conditions, the yield in ethyl oleate was 95% for immobilized enzyme. Maximum yield was obtained at 49°C, molar ratio oleic acid:ethanol of 1:3, 1.25 g lipase film or 50 U (1.03 ± 0.03 mg protein) and 30 h. Even after seven cycles of use, immobilized lipase showed 52% reduction in ester yield. Biodegradable and biorenewable film is a promising material as a support to immobilize lipases and application in biocatalysis.

Targeting chromosome 12q amplification in relapsed glioblastoma: the use of computational biological modeling to identify effective therapy-a case report.

Background: Relapsed glioblastoma (GBM) is often an imminently fatal condition with limited therapeutic options. Computation biological modeling, i.e., biosimulation, of comprehensive genomic information affords the opportunity to create a disease avatar that can be interrogated in silico with various drug combinations to identify the most effective therapies. Case Description: We report the outcome of a GBM patient with chromosome 12q amplification who achieved substantial disease remission from a novel therapy using this approach. Following next generation sequencing (NGS) was performed on the tumor specimen. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotype. In silico responses to various drug combinations were biosimulated in the disease network. Efficacy scores representing the computational effect of treatment for each strategy were generated and compared to each other to ascertain the differential benefit in drug response from various regimens. Biosimulation identified CDK4/6 inhibitors, nelfinavir and leflunomide to be effective agents singly and in combination. Upon receiving this treatment, the patient achieved a prompt and clinically meaningful remission lasting 6 months. Conclusions: Biosimulation has utility to identify active treatment combinations, stratify treatment options and identify investigational agents relevant to patients' comprehensive genomic abnormalities. Additionally, the combination of abemaciclib and nelfinavir appear promising for GBM and potentially other cancers harboring chromosome 12q amplification.

Synthesis and Antiproliferative Evaluation of 2-Deoxy-N-glycosylbenzotriazoles/imidazoles.

A series of 2-deoxy-2-iodo-α-d-mannopyranosylbenzotriazoles was synthesized using the benzyl, 4,6-benzylidene and acetyl protected D-glucal in the presence of N-iodosuccinimide (NIS). Subsequent removal of the iodine at the C-2 position using tributyltin hydride under free radical conditions afforded the 2-deoxy-α-d-glucopyranosylbenzotriazoles in moderate to high yields. This method was extended to the preparation of substituted 2-deoxy-ß-d-glucopyranosylimidazoles as well. The stereoselectivity of the addition reaction and the effect of the protecting group and temperature on anomer distribution of the benzotriazole series were also investigated. The anticancer properties of the newly synthesized compounds were evaluated in a series of viability studies using HeLa (human cervical adenocarcinoma), human breast and lung cancer cell lines. The N-[3,4,6-tri-O-benzyl-2-deoxy-α-d-glucopyranosyl]-1H-benzotriazole and the N-[3,4,6-tri-O-acetyl-2-deoxy-α-d-glucopyranosyl]-2H-benzotriazole were found to be the most potent cancer cell inhibitors at 20 µM concentrations across all four cell lines.

Combination chemotherapy versus temozolomide for patients with methylated MGMT (m-MGMT) glioblastoma: results of computational biological modeling to predict the magnitude of treatment benefit.

BACKGROUND: A randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, however the approach remains controversial and relatively under-utilized. Therefore, we sought to determine whether comprehensive genomic analysis can predict which patients would derive large, intermediate, or negligible benefits from the combination compared to single agent chemotherapy. METHODS: Comprehensive genomic information from 274 newly diagnosed patients with methylated-MGMT glioblastoma (GBM) was downloaded from TCGA. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotypes representing hallmark behavior of cancers. In silico responses to TMZ, lomustine, and combination treatment were biosimulated. Efficacy scores representing the effect of treatment for each treatment strategy were generated and compared to each other to ascertain the differential benefit in drug response. RESULTS: Differential benefits for each drug were identified, including strong, modest-intermediate, negligible, and deleterious (harmful) effects for subgroups of patients. Similarly, the benefits of combination therapy ranged from synergy, little or negligible benefit, and deleterious effects compared to single agent approaches. CONCLUSIONS: The benefit of combination chemotherapy is predicted to vary widely in the population. Biosimulation appears to be a useful tool to address the disease heterogeneity, drug response, and the relevance of particular clinical trials observations to individual patients. Biosimulation has potential to spare some patients the experience of over-treatment while identifying patients uniquely situated to benefit from combination treatment. Validation of this new artificial intelligence tool is needed.

Variations in West Nile Virus neuroinvasive infection: A case series of three patients in West Phoenix.

West Nile Virus (WNV) is the most common mosquito-borne virus in the United States and North America. Although WNV disease occurs on a spectrum ranging from a relatively benign febrile illness to life-threatening neuroinvasive disease, the clinical presentations can vary widely and thus necessitates a high degree of suspicion. Here we describe three such cases where each individual presented with a unique constellation of symptoms that made the diagnosis challenging. It is essential for physicians to be well informed on the differing symptomology so early diagnosis and supportive management can mitigate poor prognosis.

The complete mitochondrial genome of the Indian leafwing butterfly Kallima paralekta (insecta: Lepidoptera: Nymphalidae).

The Indian leafwing butterfly Kallima paralekta (Horsfield, 1829) (Nymphalidae) is an Asian forest-dwelling, leaf-mimic. Genome skimming by Illumina sequencing permitted assembly of a complete circular mitogenome of 15,200 bp from K. paralekta consisting of 79.5% AT nucleotides, 22 tRNAs, 13 protein-coding genes, two rRNAs and a control region in the typical butterfly gene order. Kallima paralekta COX1 features an atypical CGA start codon, while ATP6, COX1, COX2, ND4, ND4L, and ND5 exhibit incomplete stop codons completed by 3' A residues added to the mRNA. Phylogenetic reconstruction places K. paraleckta within the monophyletic genus Kallima, sister to Mallika in the subfamily Nymphalinae. These data support the monophyly of tribe Kallimini and contribute to the evolutionary systematics of the Nymphalidae.

Production of starch-polyester bio-support for lipases immobilization: synergistic action of itaconic acid and nanoclay.

The objective of the present work was to develop biodegradable polymeric films (starch-PBAT) as support for the immobilization of lipases using sodium montmorillonite (MMT) as a reinforcing agent (2% w/w) and itaconic acid (IA - 0.5-1.5% w/w) as a compatibilizing agent. The films were produced through a two steps blow-extrusion. The addition of MMT increased the tensile strength and Tg of the films, while the presence of IA made the films more flexible, reducing their Tg. Lipases from Burkholderia cepacia LTEB11 were immobilized in the films by the adsorption method. The ester yield (% of ethyl oleate synthesis) has shown best results (96%, 6 h) for immobilized enzyme in the MMT film and six cycles of reuse were carried out until a reduction of 50% in the catalytic activity of the enzyme.

A taxonomy of pragmatic measures of HIV preexposure prophylaxis use.

OBJECTIVES: As delivery of preexposure prophylaxis (PrEP) becomes an HIV prevention priority in the United States, standard, pragmatic measures of PrEP use are needed to compare and evaluate prevention implementation programs. By using readily available electronic health record data, we describe and compare measures of persistence and retention. DESIGN: Retrospective cohort. METHODS: Using electronic health record prescription data for patients at a large urban Federally Qualified Health Center from 2015 to 2019, we calculated measures of persistence and retention and compared them to pharmacy claims data, PrEP biomarkers, and HIV outcomes. RESULTS: Total PrEP time was 19.8 months on average. During this period, average adherence by medication prescription ratio (MRxR) was 89%; 77% of patients had an MRxR at least 85% and 90% have an MRxR at least 57%. Over the first 6 months, average proportion of days covered (PDC) at least 85% was 53% and PDC at least 57% was 57%. Prescription fill rates, based on claims data from a pharmacy partner, ranged from 45 to 60%. Using tenofovir-diphosphate as the gold standard, PDC had high sensitivity (97%) but low specificity (≤13%). As a measure of retention, over the first 6 months, 59% of patients had quarterly HIV tests. CONCLUSION: Total PrEP time is useful measure of overall persistence, while PDC can assess persistence and adherence at a specific time point. Adherence by PDC is more conservative compared with MRxR; both will overestimate true adherence. Retention in care can be measured by quarterly HIV tests. Using consistent terminology and reporting timepoints and adherence thresholds will help reporting and comparing PrEP delivery programs.

HIV Treatment Knowledge in the Context of "Treatment as Prevention" (TasP).

According to 2012 universal ART guidelines, as part of "treatment as prevention" (TasP), all people living with HIV (PLWH) should immediately initiate antiretroviral therapy post-diagnosis to facilitate viral suppression. PLWH who are virally suppressed have no risk of sexually transmitting HIV. This study used descriptive analysis of quantitative data (N = 99) and thematic analysis of qualitative interviews (n = 36) to compare participants recruited from a hospital-based detoxification (detox) unit, largely diagnosed with HIV pre-2012 (n = 63) vs. those recruited from public, urban sexual health clinics (SHCs), mainly diagnosed in 2012 or later (n = 36). Detox participants were significantly more knowledgeable than SHC participants about HIV treatment, except regarding TasP. SHC participants' desire for rapid linkage to care and ART initiation was in line with 2012 universal ART guidelines and TasP messaging regarding viral suppression. More targeted messaging to PLWH pre-2012 could ensure that all PLWH benefit from scientific advances in HIV treatment.

Long-term Surgical Outcomes After Early Definitive Spinal Fusion for Early-onset Scoliosis With Neurofibromatosis Type 1 at Mean Follow-up of 14 Years.

BACKGROUND: Several authors mentioned surgical outcome for scoliosis associated with neurofibromatosis type 1 (NF-1). However, no studies have summarized long-term surgical outcomes after surgical treatment of early-onset scoliosis (EOS) with NF-1. The purpose of this study is to evaluate the long-term surgical outcome after early definitive spinal fusion for EOS in NF-1 patients. METHODS: We performed a retrospective review on a cohort of 11 patients diagnosed with EOS associated with NF-1 between 1990 and 2009 in our hospital. The study included 7 male and 4 female NF-1 patients with a mean age at fusion surgery of 8 years 4 months who underwent early definitive spinal fusion for EOS. We reviewed radiographs, computed tomography and magnetic resonance images for each patient. The data collected included type of NF-1, Cobb angles, kyphotic angle, spinal length (T1-S1), and pulmonary function. We also evaluated progression of the dystrophic change through radiographs and computed tomography during the follow-up period. RESULTS: The mean follow-up duration was 14 years (5 y 10 mo to 25 y). All patients underwent anterior and posterior fusion surgeries in either 1 or 2 stages. Seven cases had subtotal tumor resection from the concave side followed by rib strut grafting. The mean preoperative Cobb angle of the primary curve was corrected from 71.2 to 24.1 degrees and was maintained at the final follow-up at 23.5 degrees. Mean values for preoperative and final follow-up T1-S1 heights were 30.7 and 36.2 cm, respectively. Mean values for preoperative and final follow-up % forced vital capacity (the present/the predicted) were 75.0% and 74.4%, respectively. The dystrophic change progressed in all cases during the long-term follow-up. CONCLUSIONS: Our goals for NF-1 scoliosis are to obtain deformity correction, to achieve stable instrumentation by using longer fusion levels and to attain a solid fusion mass that can tolerate continual erosion during the long-term follow-up. We achieve this by using a circumferential approach for EOS associated with NF-1. LEVEL OF EVIDENCE: Level IV-case series.

Enacted individual-level stigma, anticipated relationship stigma, and negative affect among unpartnered sexual minority individuals.

PURPOSE: To examine associations of enacted individual-level stigma and anticipated relationship stigma with negative affect among single sexual minority individuals. We hypothesized that enacted individual-level stigma and anticipated relationship stigma would be positively associated with negative affect. We also explored possible mediation models of how these variables might relate. METHODS: A nation-wide online survey was completed by 154 single sexual minority individuals 18+ years old, measuring enacted individual-level stigma, anticipated relationship stigma, and negative affect. RESULTS: There were significant, positive bivariate associations of enacted individual-level stigma with anticipated relationship stigma and negative affect. In path model analyses, there was support for enacted individual-level stigma mediating an indirect pathway between anticipated relationship stigma and negative affect, as well as support for enacted individual-level stigma simultaneously predicting anticipated relationship stigma and negative affect. CONCLUSIONS: Findings expand the body of theoretical work examining multidimensional aspects and mechanisms of stigma. Results suggest that while anticipated relationship stigma is not directly associated with negative affect among single sexual minority individuals, it may still be relevant for well-being among these individuals through its association with enacted individual-level stigma. Clinicians and public health officials may consider addressing multiple forms of stigma, including both individual-level and relationship-based stigma.

Modeling Interpersonal Correlates of Condomless Anal Sex among Gay and Bisexual Men: An Application of Attachment Theory.

The existing literature has identified that beliefs about the interpersonal meaning of condom use are a significant predictor of condomless anal sex (CAS). Some have suggested that condom use in this context may function as a form of nonverbal communication. This study utilized attachment theory as a framework and tested a hypothesized model linking adult attachment to CAS through communication skills and condom expectancies. An online survey was completed by 122 single, HIV-negative gay and bisexual (GB) men living in the U.S. They completed measures of adult attachment (anxious and avoidant), condom expectancies regarding intimacy and pleasure interference, communication skills, self-assessed mate value, and recent CAS with casual partners. There was a significant, positive bivariate association between anxious attachment and receptive CAS. In path model analyses, two over-arching pathways emerged. In the other-oriented pathway, anxious attachment, self-perceived mate value, and emotional communication predicted the belief that condoms interfere with intimacy. In turn, intimacy interference expectancies were positively associated with the odds of receptive CAS. In the self-oriented pathway, assertive communication skills mediated a link between avoidant attachment and the belief that condoms interfere with sexual pleasure. Pleasure interference expectancies were positively associated with the odds of insertive CAS. The findings highlight the importance of relational or interpersonal concerns in sexual risk-taking among single GB men. Attachment theory may serve as a framework for organizing these interpersonal correlates of CAS. Results are consistent with the conceptualization of condom use as a form of nonverbal attachment-related behavior. Implications for sexual health and risk-reduction interventions are explored in this context.

Synchronous Onset of Breast and Pancreatic Cancers: Results of Germline and Somatic Genetic Analysis.

BACKGROUND: Synchronous cancers have occasionally been detected at initial diagnosis among patients with breast and ovarian cancer. However, simultaneous coexistence and diagnosis of breast and pancreas cancer has not previously been reported. CASE REPORT: Paternal transmission of a germline BRCA2 mutation to a patient who was diagnosed at age 40 with locally advanced breast and pancreas cancer is presented. Somatic genomic analysis of both cancers with next-generation DNA sequencing confirmed the germline result and reported a variety of variants of unknown significance alterations, of which two were present in both the breast and pancreas cancers. DISCUSSION: The possibility that genomic alterations could have been responsible for modulating the phenotypic or clinical expression of this rare presentation is considered. The authors call attention to the practice of privatizing the clinicogenetic information gained from genetic testing and call for health policy that will facilitate sharing in order to advance the outcomes of patients diagnosed with hereditary cancers.