Cytotoxicity of a Ti(IV) compound is independent of serum proteins.

Titanium(IV) compounds are excellent anticancer drug candidates, but they have yet to find success in clinical applications. A major limitation in developing further compounds has been a general lack of understanding of the mechanism governing their bioactivity. To determine factors necessary for bioactivity, we tested the cytotoxicity of different ligand compounds in conjunction with speciation studies and mass spectrometry bioavailability measurements. These studies demonstrated that the Ti(IV) compound of N,N'-di(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) is cytotoxic to A549 lung cancer cells, unlike those of citrate and naphthalene-2,3-diolate. Although serum proteins are implicated in the activity of Ti(IV) compounds, we found that these interactions do not play a role in [TiO(HBED)](-) activity. Subsequent compound characterization revealed ligand properties necessary for activity. These findings establish the importance of the ligand in the bioactivity of Ti(IV) compounds, provides insights for developing next-generation Ti(IV) anticancer compounds, and reveal [TiO(HBED)](-) as a unique candidate anticancer compound.

A breath fungal secondary metabolite signature to diagnose invasive aspergillosis.

BACKGROUND: Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection. METHODS: Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples. RESULTS: The monoterpenes camphene, α- and ß-pinene, and limonene, and the sesquiterpene compounds α- and ß-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, ß-trans-bergamotene, a ß-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%). CONCLUSIONS: In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.

Metaplastic breast cancer: A review.

Metaplastic breast cancer (MpBC) is an uncommon aggressive malignancy that is associated with a poor prognosis. Due to its rarity, the relationships between the clinical and pathological features of MpBC, treatment approach, and clinical outcomes remain underexplored. In the following review article, we synthesize the existing data on the clinical, pathological and genomic features, management, and outcomes of MpBC. We also identify potential targets for future clinical trials.

Contrast-enhanced 4D-MRI for internal target volume generation in treatment planning for liver tumors.

BACKGROUND: Liver tumors are often invisible on four-dimensional commuted tomography (4D-CT). Imperfect imaging surrogates are used to estimate the tumor motion. Here, we assessed multiple 4D magnetic resonance (MR) binning algorithms for directly visualizing liver tumor motion for radiotherapy planning. METHODS: Patients were simulated using a 3 Tesla MR and CT scanner. Three prototype binning algorithms (phase, amplitude, and two-directional) were applied to the 4D-MRIs, and the image quality was assessed using a qualitative clarity score and quantitative sharpness score. Radiation plans were generated for internal target volumes (ITVs) derived using 4D-MRI and 4D-CT, and the dosimetry of targets were compared. Paired t-tests were used to compare sharpness scores and dosimetric data. RESULTS: Twelve patients with 17 liver tumors were scanned between May and November 2021. Compared to phase binning, two-directional demonstrated equal or better clarity and sharpness scores (end-expiration: 0.33 vs 0.38, p = 0.018, end-inspiration: 0.28 vs 0.31, p = 0.010). Compared to amplitude binning, two-directional binning captured hysteresis of ≥ 3 mm in 35 % of patients. Evaluation of dosimetry CT-optimized plans revealed that PTV coverage of MR-derived targets were significantly lower than CT-derived targets (PTV receiving 90 % of prescription: 75.56 % vs 89.38 %, p = 0.002). CONCLUSION: Using contrast-enhanced 4D-MRI is feasible for directly delineating liver tumors throughout the respiratory cycle. The current standard of using radiation plans optimized for 4D-CT-derived targets achieved lower coverage of directly visualized MRI targets, suggesting that adopting MRI for motion management may improve radiation treatment of liver lesions and reduce the risk of marginal misses.

Residents-as-Teachers Curriculum for Radiation Oncology: A Targeted Needs Assessment.

PURPOSE: Achieving competency as educators is increasingly recognized as a critical part of residents' training in graduate medical education across specialties. In addition to teaching medical students, radiation oncology residents often play a vital role in peer and interprofessional education. We conducted a survey to identify the needs of radiation oncology residents for developing skills in teaching. METHODS AND MATERIALS: An anonymous, web-based survey was developed and distributed to resident physicians at US radiation oncology programs. Analyses describe respondent demographics, experiences with teaching, and interest in various aspects of a formal "residents-as-teachers" curriculum. RESULTS: There were 171 completed survey responses (27.5% response rate). A total of 146 residents (85.4%) reported receiving no formal training in teaching before residency, and 121 (70.8%) reported no formal training during residency. Residents who had formal training in teaching were significantly more likely to be "quite" or "extremely" confident about teaching compared with residents who had no prior formal training (76.0% vs 51.4%; P = .022). Residents most commonly taught other residents and medical students (163 [95.3%] and 160 [93.6%] respondents, respectively). The most common settings for teaching were one-on-one teaching (164 respondents [95.9%]), small-group lectures (135 respondents [78.9%]), and intradepartmental lectures (136 respondents [79.5%]). In response to open-ended questions regarding desired teaching opportunities and domains for teaching development, many residents expressed a lack of confidence in teaching and were interested in improvement across many aspects of teaching. CONCLUSIONS: Radiation oncology residents are expected and desire to teach in a multitude of settings across a wide variety of audiences. However, a significant proportion of radiation oncology residents lack formal training and rarely receive feedback for their teaching skills. The results of this national survey support the development of a residents-as-teachers curriculum for radiation oncology residents that would address the needs for and significant interest in this area.

A global metabolite profiling approach to identify protein-metabolite interactions.

Understanding the biochemical functions of proteins is an important factor in elucidating their cellular and physiological functions. Due to the predominance of biopolymer interactions in biology, many methods have been designed to interrogate and identify biologically relevant interactions that proteins make to DNA, RNA, and other proteins. Complementary approaches that can elucidate binding interactions between proteins and small molecule metabolites will impact the understanding of protein-metabolite interactions and fill a need that is outside the scope of current methods. Here, we demonstrate the ability to identify natural protein-metabolite interactions from complex metabolite mixtures by combining a protein-mediated small molecule enrichment step with a global metabolite profiling platform.

Association Between Androgen Deprivation Therapy and Patient-reported Depression in Men With Recurrent Prostate Cancer.

BACKGROUND: Previous studies have reported conflicting results on the relationship between androgen deprivation therapy (ADT) and the risk of depression. We assessed whether ADT is associated with depression in a unique data set of men with recurrent prostate cancer. PATIENTS AND METHODS: We studied a cohort of 656 men in the prospective COMPARE (Comprehensive, Multicenter, Prostate Adenocarcinoma) registry who experienced biochemical recurrence after radiation therapy (RT) only, radical prostatectomy (RP) with or without RT, or ADT with RP or RT. Multivariable logistic regression was used to determine the relationship between the modality of treatment and patient-reported depression. RESULTS: Of 656 men, 44 (6.7%) experienced depression. The prevalence of depression stratified by treatment was 3.2% for RT only, 5.9% for RP with or without RT, and 9.1% for ADT plus RP or RT. Compared with RT-only, ADT plus RP or RT was associated with a significantly increased rate of depression (P = .031) and RP with or without RT was not (P = .195). On multivariate analysis adjusting for age and baseline comorbidities, the receipt of ADT was associated with an increased risk of depression (odds ratio, 3.29; 95% confidence interval, 1.11-9.76; P = .032) compared with RT only. No statistically significant difference was found in the risk of depression for men who received RP with or without RT versus RT only (odds ratio, 2.12; 95% confidence interval, 0.68-6.65; P = .19). CONCLUSION: Men with recurrent prostate cancer who underwent ADT were 3 times more likely to report experiencing depression. Treating physicians should discuss depression as a possible side effect when considering the use of ADT and should screen for depression in men who have received ADT.