Development of New CD38 Targeted Peptides for Cancer Imaging.

PURPOSE: Multiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges. PROCEDURES: Using phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems. RESULTS: The CD38-targeted bioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 - 6.6 MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291 nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4 h. Clearance from non-target organs occurred within 60 min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4 h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1 h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4 h). CONCLUSIONS: The novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

Advancements in the development of radiopharmaceuticals for nuclear medicine applications in the treatment of bone metastases.

Bone metastases are a painful and complex condition that overwhelmingly impacts the prognosis and quality of life of cancer patients. Over the years, nuclear medicine has made remarkable progress in the diagnosis and management of bone metastases. This review aims to provide a comprehensive overview of the recent advancements in nuclear medicine for the diagnosis and management of bone metastases. Furthermore, the review explores the role of targeted radiopharmaceuticals in nuclear medicine for bone metastases, focusing on radiolabeled molecules that are designed to selectively target biomarkers associated with bone metastases, including osteocytes, osteoblasts, and metastatic cells. The applications of radionuclide-based therapies, such as strontium-89 (Sr-89) and radium-223 (Ra-223), are also discussed. This review also highlights the potential of theranostic approaches for bone metastases, enabling personalized treatment strategies based on individual patient characteristics. Importantly, the clinical applications and outcomes of nuclear medicine in osseous metastatic disease are discussed. This includes the assessment of treatment response, predictive and prognostic value of imaging biomarkers, and the impact of nuclear medicine on patient management and outcomes. The review identifies current challenges and future perspectives on the role of nuclear medicine in treating bone metastases. It addresses limitations in imaging resolution, radiotracer availability, radiation safety, and the need for standardized protocols. The review concludes by emphasizing the need for further research and advancements in imaging technology, radiopharmaceutical development, and integration of nuclear medicine with other treatment modalities. In summary, advancements in nuclear medicine have significantly improved the diagnosis and management of osseous metastatic disease and future developements in the integration of innovative imaging modalities, targeted radiopharmaceuticals, radionuclide production, theranostic approaches, and advanced image analysis techniques hold great promise in improving patient outcomes and enhancing personalized care for individuals with bone metastases.

Desulfoferrobacter suflitae gen. nov., sp. nov., a novel sulphate-reducing bacterium in the Deltaproteobacteria capable of autotrophic growth with hydrogen or elemental iron.

A mesophilic sulphate-reducing micro-organism, able to grow chemolithoautotrophically with H2/CO2 (20 : 80) and with elemental iron as a sole electron donor, was isolated from a consortium capable of degrading long-chain paraffins and designated strain DRH4T. Cells were oval shaped often with bright refractile cores and occurred singly or in pairs. The cells formed pili. Strain DRH4T could grow chemolithoautotrophically with H2/CO2 or elemental iron and chemoorganotrophically utilizing a number of organic substrates, such as fatty acids from formate to octanoate (C1-C8). Sulphate and thiosulphate served as terminal electron acceptors, but sulphite and nitrate did not. Optimal growth was observed from 37 to 40 °C and pH from 6.5 to 7.2. Strain DRH4T did not require NaCl for growth and could proliferate under a broad range of salinities from freshwater (1 g l-1 NaCl) to seawater (27 g l-1 NaCl) conditions. The genomic DNA G+C content was 54.46 mol %. Based on 16S rRNA gene sequence analysis. strain DRH4T was distinct from previously described Deltaproteobacteria species exhibiting the closest affiliation to Desulforhabdus amnigena ASRB1T, Syntrophobacterium sulfatireducens TB8106T and Desulfovirga adipica 12016T with 93.35, 93.42 and 92.85 % similarity, respectively. Strain DRH4T showed significant physiological differences with the aforementioned organisms. Based on physiological differences and phylogenetic comparisons, we propose to classify DRH4T as the type strain (=DSM 113 455T=JCM 39 248T) of a novel species of a new genus with the name Desulfoferrobacter suflitae gen. nov., sp. nov.

Recognising and healing emotional wounds of child labourers: call to action based on the evidence and stakeholder views from India and Nepal.

Child labourers are at risk of poorer mental health and once rescued require urgent mental health interventions to ameliorate the long-term impact. In our review, only two published scientific studies evaluated custom-made interventions; other programmes were obtained from non-governmental organisations (NGOs), which need rigorous trial evaluation. We also sought the viewpoints of stakeholders working directly with rescued young people, as well as consulting young people with lived experiences of child labour. We propose that psychoeducational interventions aimed at employees working directly with young people could represent a fruitful approach for low- and middle-income countries in the Asia-Pacific region but also more generally.

Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival.

Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which is increasingly treatable but still incurable. In 90% of MM patients, severe osteolysis results from pathological interactions between MM cells and the bone microenvironment. Delineating specific molecules and pathways for their role in cancer supportive interactions in the BM is vital for developing new therapies. Very Late Antigen 4 (VLA4, integrin α4ß1) is a key player in cell-cell adhesion and signaling between MM and BM cells. We evaluated a VLA4 selective near infrared fluorescent probe, LLP2A-Cy5, for in vitro and in vivo optical imaging of VLA4. Furthermore, two VLA4-null murine 5TGM1 MM cell (KO) clones were generated by CRISPR/Cas9 knockout of the Itga4 (α4) subunit, which induced significant alterations in the transcriptome. In contrast to the VLA4+ 5TGM1 parental cells, C57Bl/KaLwRij immunocompetent syngeneic mice inoculated with the VLA4-null clones showed prolonged survival, reduced medullary disease, and increased extramedullary disease burden. The KO tumor foci showed significantly reduced uptake of LLP2A-Cy5, confirming in vivo specificity of this imaging agent. This work provides new insights into the pathogenic role of VLA4 in MM, and evaluates an optical tool to measure its expression in preclinical models.

Quantitative tumor depth determination using dual wavelength excitation fluorescence.

Quantifying solid tumor margins with fluorescence-guided surgery approaches is a challenge, particularly when using near infrared (NIR) wavelengths due to increased penetration depths. An NIR dual wavelength excitation fluorescence (DWEF) approach was developed that capitalizes on the wavelength-dependent attenuation of light in tissue to determine fluorophore depth. A portable dual wavelength excitation fluorescence imaging system was built and tested in parallel with an NIR tumor-targeting fluorophore in tissue mimicking phantoms, chicken tissue, and in vivo mouse models of breast cancer. The system showed high accuracy in all experiments. The low cost and simplicity of this approach make it ideal for clinical use.

Genome Sequence of Clostridium sp. Strain P21, a CO-Fermenting Acetogen Isolated from Old Hay.

Here, we report the genome sequence of Clostridium sp. strain P21, isolated from old hay from Stillwater, Oklahoma. This announcement describes the generation and annotation of the 5.6-Mb genomic sequence of strain P21, which will aid in studies targeting genes involved in the enhancement of acid-alcohol production.

Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma.

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.

The Complete Genome Sequence of n-Alkane-Degrading Desulfoglaeba alkanexedens ALDC Reveals Multiple Alkylsuccinate Synthase Gene Clusters.

Anaerobic alkane metabolism is critical in multiple environmental and industrial sectors, including environmental remediation, energy production, refined fuel stability, and biocorrosion. Here, we report the complete gap-closed genome sequence for a model n-alkane-degrading anaerobe, Desulfoglaeba alkanexedens ALDC.

Investigating Instructor Talk in Novel Contexts: Widespread Use, Unexpected Categories, and an Emergent Sampling Strategy.

Instructor Talk-noncontent language used by instructors in classrooms-is a recently defined and promising variable for better understanding classroom dynamics. Having previously characterized the Instructor Talk framework within the context of a single course, we present here our results surrounding the applicability of the Instructor Talk framework to noncontent language used by instructors in novel course contexts. We analyzed Instructor Talk in eight additional biology courses in their entirety and in 61 biology courses using an emergent sampling strategy. We observed widespread use of Instructor Talk with variation in the amount and category type used. The vast majority of Instructor Talk could be characterized using the originally published Instructor Talk framework, suggesting the robustness of this framework. Additionally, a new form of Instructor Talk-Negatively Phrased Instructor Talk, language that may discourage students or distract from the learning process-was detected in these novel course contexts. Finally, the emergent sampling strategy described here may allow investigation of Instructor Talk in even larger numbers of courses across institutions and disciplines. Given its widespread use, potential influence on students in learning environments, and ability to be sampled, Instructor Talk may be a key variable to consider in future research on teaching and learning in higher education.

Community succession in an anaerobic long-chain paraffin-degrading consortium and impact on chemical and electrical microbially influenced iron corrosion.

Community compositional changes and the corrosion of carbon steel in the presence of different electron donor and acceptor combinations were examined with a methanogenic consortium enriched for its ability to mineralize paraffins. Despite cultivation in the absence of sulfate, metagenomic analysis revealed the persistence of several sulfate-reducing bacterial taxa. Upon sulfate amendment, the consortium was able to couple C28H58 biodegradation with sulfate reduction. Comparative analysis suggested that Desulforhabdus and/or Desulfovibrio likely supplanted methanogens as syntrophic partners needed for C28H58 mineralization. Further enrichment in the absence of a paraffin revealed that the consortium could also utilize carbon steel as a source of electrons. The severity of both general and localized corrosion increased in the presence of sulfate, regardless of the electron donor utilized. With carbon steel as an electron donor, Desulfobulbus dominated in the consortium and electrons from iron accounted for ∼92% of that required for sulfate reduction. An isolated Desulfovibrio spp. was able to extract electrons from iron and accelerate corrosion. Thus, hydrogenotrophic partner microorganisms required for syntrophic paraffin metabolism can be readily substituted depending on the availability of an external electron acceptor and a single paraffin-degrading consortium harbored microbes capable of both chemical and electrical microbially influenced iron corrosion.

Incorporating intervention fidelity components into randomized controlled trials promoting exercise adherence in heart failure patients.

Intervention fidelity (IF) in behavioral interventions is complicated by their dynamic and interactive nature. Translation of the outcomes to practice may be diminished by lack of fidelity. The purpose of this paper is to describe a systematic, evidence-based IF approach in a complex, multicomponent behavioral change study. The National Institutes of Health-funded randomized controlled trial was designed to evaluate the effect of an adherence to exercise intervention. Two hundred forty-six heart failure patients from two sites were enrolled. This description of the study-specific standardized protocol, the data collection methods used, findings from the plan, and the discussion of the successes and challenges contributes to the advancement of IF implementation science.

Effects of sample preservation on marine microbial diversity analysis.

Three replicate seawater samples were collected on three different days, filtered immediately and preserved with one of two guanidinium thiocyanate-based preservatives (DNAzol™ or RNA Lysis Buffer™ plus ß-mercaptoethanol (RLA+)) and were kept frozen while being shipped to a lab. In parallel, a carboy of seawater was collected on each of the three days and maintained at ambient temperature while being shipped to a lab. Upon receipt the samples were filtered and treated in the same manner as for immediate preservation. Significantly more DNA was obtained from samples immediately preserved with DNAzol than the corresponding shipped samples for 2 of the 3 days. More DNA was extracted from DNAzol preserved samples but more RNA was obtained from RLA+ preserved samples. A protocol was designed to extract both DNA and RNA from split samples preserved with RLA+ and cDNA was synthesized from the RNA. Three high-throughput 16S rRNA gene libraries were constructed, one from DNA preserved with DNAzol, one from DNA preserved with RLA+ and one from cDNA (RLA+ preserved). Greater alpha diversity was found for libraries constructed from immediately preserved vs. shipped samples for both preservation types, with immediate preservation with DNAzol obtaining the highest level of diversity. Libraries constructed from immediately preserved (RLA+) DNA had greater alpha diversity than libraries constructed from shipped preserved (RLA+) DNA or cDNA. Unifrac measures of beta diversity showed clearer separation of sample types and a greater % variance explained for weighted than for unweighted principal coordinate analysis (PCoA) plots, indicating sample types varied more in their relative abundance of taxa than the presence/absence of particular taxa. We recommend immediate preservation of seawater samples, with DNAzol as the preferred preservative if quantification via qPCR will be performed or the highest alpha diversity is desired but preservation with RLA+ if RNA will be extracted.

Patient-Selected Strategies for Post Cardiac Rehabilitation Exercise Adherence in Heart Failure.

PURPOSE: The aim of this study was to evaluate the use of patient-selected exercise adherence strategies following cardiac rehabilitation (CR). DESIGN: Twenty patients with heart failure (HF) were recruited and randomly assigned to the intervention or control group at completion of CR. METHODS: The intervention included the use of six adherence strategies (logs, graphs, pedometers, phone follow-up, education, and a letter from CR staff), which were provided for 6 weeks post CR and during home-based exercise. After 6 weeks, the intervention group selected strategies to continue, and only those were provided for the last 6 weeks. At 12 weeks, patients were retested. FINDINGS: Patients with HF demonstrated improvement in distance walked and less HF symptoms and adhered to exercise at levels recommended during CR. CONCLUSION: Inclusion of patient-selected adherence strategies supports continued exercise and helps to sustain physiological improvements. CLINICAL RELEVANCE: Results from this study have implications for CR programs serving HF patients and provide insight into adherence strategies.

Effects of the HEART Camp Trial on Adherence to Exercise in Patients With Heart Failure.

BACKGROUND: Few exercise training studies in patients with heart failure (HF) report adherence to guideline-recommended 150 minutes of moderate-intensity exercise per week, and no studies have focused on a primary outcome of adherence. METHODS AND RESULTS: This randomized controlled trial evaluated the effect of a multicomponent intervention, Heart Failure Exercise and Resistance Training (HEART) Camp, on adherence to exercise (after 6, 12, and 18 months) compared with an enhanced usual care (EUC) group. Patients (n = 204) were 55.4% male, overall average age was 60.4 years, and 47.5% were nonwhite. The HEART Camp group had significantly greater adherence at 12 (42%) and 18 (35%) months compared with the EUC group (28% and 19%, respectively). No significant difference (P > .05) was found at 6 months. The treatment effect did not differ based on patient's age, race, gender, marital status, type of HF (preserved or reduced ejection fraction) or New York Heart Association functional class. Left ventricular ejection fraction (LVEF) significantly moderated the treatment effect, with greater adherence at higher LVEF. CONCLUSIONS: The multicomponent HEART Camp intervention showed efficacy with significant effects at 12 months and 18 months. Adherence levels remained modest, indicating a need for additional research to address methods and strategies to promote adherence to exercise in patients with HF.

A semi-continuous system for monitoring microbially influenced corrosion.

Microbially influenced corrosion (MIC), also known as biocorrosion, has significant impacts on the environment and economy. Typical systems to study biocorrosion are either dynamic (once-through flow) or static (serum bottle incubations). Dynamic systems can be materials and personnel intensive, while static systems quickly become nutrient limiting and exhibit long incubations. A semi-continuous biocorrosion cell was developed to address these issues. Low carbon shim steel was used as a test surface. Initial results revealed that 50 ppm glutaraldehyde (GLT), a common oil field biocide, in an abiotic cell was 3.6 times more corrosive (24.5 × 10-3 mm/y) than a biocorrosion cell inoculated with a sulfate-reducing bacteria (SRB) enrichment (6.73 × 10-3 mm/y). The SRB inoculated cell treated with GLT (50 ppm) reduced the corrosion rate from 6.73 × 10-3 mm/y to 3.68 × 10-3 mm/y. It was hypothesized that a biocide-surfactant combination would enhance biocide activity, thereby lowering corrosion in a semi-continuous biocorrosion cell. The biocide and surfactant were GLT (30 ppm) and Tween 80 (TW80; 100 ppm). MIC of SRB increased in the presence of a non-inhibitory concentration of GLT (23.4 × 10-3 mm/y), compared to the untreated +SRB condition (8.29 × 10-3 mm/y). The non-ionic surfactant alone reduced MIC (4.57 × 10-3 mm/y) and even more so in combination with GLT (3.69 × 10-3 mm/y). Over 50% of 16S rDNA sequences in the biofilm on the test surface were identified as belonging to the genera Desulfovibrio and Desulfomicrobium. The utility of a semi-continuous system for MIC studies and biocide testing was demonstrated. The concept of regular partial medium replacement is applicable to different corrosion cell and corrosion coupon geometries. Biocide-surfactant combinations may have the potential to reduce the concentration of biocides used in the field. In addition, a semi-defined medium for enumerating Acid-Producing Bacteria (APB) was developed, resulting in higher recoveries compared to a standard phenol red medium (e.g., 1.1 × 104 APB/cm2 vs < 4 × 10-1 APB/cm2).

Accelerometer-Measured Daily Activity Levels and Related Factors in Patients With Heart Failure.

BACKGROUND: Few studies report objective accelerometer-measured daily physical activity levels in patients with heart failure (HF). OBJECTIVE: We examined baseline accelerometer-measured physical activity from the Heart Failure Exercise and Resistance Training Camp trial, a federally funded (R01-HL112979) 18-month intervention study to promote adherence to exercise in patients with HF. Factors associated with physical activity levels were also explored. METHODS: Patients with diagnosed HF (stage C chronic HF confirmed by echocardiography and clinical evaluation) were recruited from 2 urban medical centers. Physical activity energy expenditure and the number of minutes of moderate or vigorous physical activity (MVPA) were obtained from 7 full days of measurement with the accelerometer (Actigraph Model GT3X, Pensacola, Florida) for 182 subjects who met minimum valid wear time parameters. Additional measures of health-related factors were included to explore the association with physical activity levels. RESULTS: Subjects had 10.2 ± 10.5 minutes of MVPA per day. Total physical activity energy expenditure was 304 ± 173 kcal on average per day. There were 23 individuals (12.6%) who met the recommended goal of 150 minutes of MVPA per week. Men, whites, New York Heart Association class II, and subjects with better physical function had significantly higher levels of activity. CONCLUSIONS: Consistent with previous research, patients with HF are not meeting recommended guidelines for 150 minutes of MVPA per week.

Anaerobic biodegradation of biofuels and their impact on the corrosion of a Cu-Ni alloy in marine environments.

Fuel biodegradation linked to sulfate reduction can lead to corrosion of the metallic infrastructure in a variety of marine environments. However, the biological stability of emerging biofuels and their potential impact on copper-nickel alloys commonly used in marine systems has not been well documented. Two potential naval biofuels (Camelina-JP5 and Fisher-Tropsch-F76) and their petroleum-derived counterparts (JP5 and F76) were critically assessed in seawater/sediment incubations containing a metal coupon (70/30 Cu-Ni alloy). Relative to a fuel-unamended control (1.2 ±â€¯0.4 µM/d), Camelina-JP5 (86.4 ±â€¯1.6 µM/d) and JP5 (77.6 ±â€¯8.3 µM/d) stimulated much higher rates of sulfate reduction than either FT-F76 (11.4 ±â€¯2.7 µM/d) or F76 (38.4 ±â€¯3.7 µM/d). The general corrosion rate (r2 = 0.91) and pitting corrosion (r2 = 0.92) correlated with sulfate loss in these incubations. Despite differences in microbial community structure on the metal or in the aqueous or sediment phases, sulfate reducing bacteria affiliated with Desulfarculaceae and Desulfobacteraceae became predominant upon fuel amendment. The identification of alkylsuccinates and alkylbenzylsuccinates attested to anaerobic metabolism of fuel hydrocarbons. Sequences related to Desulfobulbaceae were highly enriched (34.2-64.8%) on the Cu-Ni metal surface, regardless of whether the incubation received a fuel amendment. These results demonstrate that the anaerobic metabolism of biofuel linked to sulfate reduction can exacerbate the corrosion of Cu-Ni alloys. Given the relative lability of Camelina-JP5, particular precaution should be taken when incorporating this hydroprocessed biofuel into marine environments serviced by a Cu-Ni metallic infrastructure.