Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently
and the ...main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.
Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis ...of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach.
Twenty HPV+ and 20 HPV- laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings.
HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors.
These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
Objective
To update previously reported outcomes of modified‐template post‐chemotherapy retroperitoneal lymph node dissection (PC‐RPLND) in appropriately selected patients with metastatic ...non‐seminomatous germ cell tumour (NSGCT), as our previous report was criticised for short follow‐up and so we now provide a long‐term update on this cohort.
Patients and Methods
In all, 100 patients with normal serum markers after cisplatin‐based chemotherapy and residual retroperitoneal tumour underwent modified PC‐RPLND between 1991 and 2004. Using a prospectively managed institutional testicular cancer database, long‐term follow‐up was obtained.
Results
As previously reported, 43 patients underwent a right‐modified template, 18 patients underwent a full‐left‐modified template, and 39 patients underwent a left‐modified template. The updated long‐term median follow‐up for the entire cohort is 125 months. Seven patients developed recurrent disease with a median (range) time to recurrence of 11 (6–102) months, and one patient died from recurrent disease in the chest 4 years after surgery. All recurrences were outside the boundaries of a full‐bilateral template RPLND, with the most common location of recurrence being the chest. The 5‐ and 10‐year recurrence‐free survival rates were 93% and 92%, respectively. The overall survival at 10 years was 99%.
Conclusions
In appropriately selected patients with low‐volume disease before and after chemotherapy, a modified template has durable long‐term efficacy without risk of in‐field recurrences at a median follow‐up of 125 months.
SARS-CoV-2 genomic sequencing efforts have scaled dramatically to address the current global pandemic and aid public health. However, autonomous genome annotation of SARS-CoV-2 genes, proteins, and ...domains is not readily accomplished by existing methods and results in missing or incorrect sequences. To overcome this limitation, we developed a novel semi-supervised pipeline for automated gene, protein, and functional domain annotation of SARS-CoV-2 genomes that differentiates itself by not relying on the use of a single reference genome and by overcoming atypical genomic traits that challenge traditional bioinformatic methods. We analyzed an initial corpus of 66,000 SARS-CoV-2 genome sequences collected from labs across the world using our method and identified the comprehensive set of known proteins with 98.5% set membership accuracy and 99.1% accuracy in length prediction, compared to proteome references, including Replicase polyprotein 1ab (with its transcriptional slippage site). Compared to other published tools, such as Prokka (base) and VAPiD, we yielded a 6.4- and 1.8-fold increase in protein annotations. Our method generated 13,000,000 gene, protein, and domain sequences-some conserved across time and geography and others representing emerging variants. We observed 3362 non-redundant sequences per protein on average within this corpus and described key D614G and N501Y variants spatiotemporally in the initial genome corpus. For spike glycoprotein domains, we achieved greater than 97.9% sequence identity to references and characterized receptor binding domain variants. We further demonstrated the robustness and extensibility of our method on an additional 4000 variant diverse genomes containing all named variants of concern and interest as of August 2021. In this cohort, we successfully identified all keystone spike glycoprotein mutations in our predicted protein sequences with greater than 99% accuracy as well as demonstrating high accuracy of the protein and domain annotations. This work comprehensively presents the molecular targets to refine biomedical interventions for SARS-CoV-2 with a scalable, high-accuracy method to analyze newly sequenced infections as they arise.
This study examined the association of three specific COVID‐19–related workplace stressors (percentage of nursing work with COVID‐positive COVID+ patients, number of COVID‐19–related patient deaths ...witnessed, and living separately from family for safety) and their associations with posttraumatic stress symptoms (PTSS) and symptoms of major depressive disorder (MDD) and generalized anxiety disorder (GAD) among 391 nurses (93.6% White, 93.4% utilize she/her pronouns). Cross‐sectional data were collected via an online survey. Institutional betrayal (i.e., the perception that an institution failed to protect a member who depends on and trusts it) was examined as a moderator of these associations. Although institutional betrayal was not a significant moderator in the three individual models, it held small‐to‐medium–sized positive main effects with PTSS and symptoms of GAD and MDD in both the individual and combined models. In the individual models, the percentage of nursing work with COVID+ patients was significantly positively associated with all three mental health conditions, f2 = .019–.195, whereas it only showed a significant effect with PTSS in the combined model, f2 = .138. Living separately from family was significantly positively associated with PTSS and MDD symptoms in both the individual, f2 = .037 and .015, respectively, and combined models, f2 = .025 and .013, respectively. Number of patient deaths held a significant positive association with PTSS alone, f2 = .022, in the individual model only. The findings are discussed in light of ways in which health care settings can better support and prioritize mental health among nursing staff.
Desorption electrospray ionization mass spectrometry (DESI-MS) has been successfully used to discriminate between normal and cancerous human tissue from different anatomical sites. On the basis of ...this, DESI-MS imaging was used to characterize human seminoma and adjacent normal tissue. Seminoma and adjacent normal paired human tissue sections (40 tissues) from 15 patients undergoing radical orchiectomy were flash frozen in liquid nitrogen and sectioned to 15 μm thickness and thaw mounted to glass slides. The entire sample was two-dimensionally analyzed by the charged solvent spray to form a molecular image of the biological tissue. DESI-MS images were compared with formalin-fixed, hematoxylin and eosin (H&E) stained slides of the same material. Increased signal intensity was detected for two seminolipids seminolipid (16:0/16:0) and seminolipid (30:0) in the normal tubule testis tissue; these compounds were undetectable in seminoma tissue, as well as from the surrounding fat, muscle, and blood vessels. A glycerophosphoinositol PI(18:0/20:4) was also found at increased intensity in the normal testes tubule tissue when compared with seminoma tissue. Ascorbic acid (i.e., vitamin C) was found at increased amounts in seminoma tissue when compared with normal tissue. DESI-MS analysis was successfully used to visualize the location of several types of molecules across human seminoma and normal tissues. Discrimination between seminoma and adjacent normal testes tubules was achieved on the basis of the spatial distributions and varying intensities of particular lipid species as well as ascorbic acid. The increased presence of ascorbic acid within seminoma compared with normal seminiferous tubules was previously unknown.
Preclinical data suggest that poly(ADP-ribose) polymerase (PARP) inhibitors have synergistic activity when combined with immune checkpoint inhibitors (ICIs); however, it is unknown which tumor types ...or molecular subtypes may benefit from this combination.
To investigate responses associated with the combination of avelumab and talazoparib in different tumor types and/or molecular subtypes.
In this phase 1b and 2 basket nonrandomized controlled trial, patients with advanced solid tumors were enrolled in the following cohorts: non-small cell lung cancer (NSCLC); DNA damage response (DDR)-positive NSCLC; triple-negative breast cancer (TNBC); hormone receptor-positive, human epidermal growth factor receptor 2 (ERBB2)-negative, DDR-positive breast cancer; recurrent, platinum-sensitive ovarian cancer (OC); recurrent, platinum-sensitive, BRCA1/2-altered OC; urothelial cancer; metastatic castration-resistant prostate cancer (mCRPC); DDR-positive mCRPC; and BRCA1/2- or ATM-altered solid tumors. Data were analyzed between June 17, 2021, and August 6, 2021.
All patients in phases 1b and 2 received avelumab plus talazoparib.
The phase 1b primary end point was dose-limiting toxic effects. The phase 2 primary end point was objective response, measured as objective response rate (ORR). Secondary end points included safety, time to response, duration of response (DOR), progression-free survival, time to prostate-specific antigen progression and PSA response of 50% or greater (for mCRPC), cancer antigen 125 response (for OC), pharmacokinetics, immunogenicity, and biomarkers.
A total of 223 patients (mean SD age, 63.2 11.0 years; 117 52.5% men) were treated, including 12 patients in phase 1b and 211 patients in phase 2. The recommended phase 2 dose was avelumab 800 mg every 2 weeks plus talazoparib 1 mg once daily. In phase 2, the ORR was 18.2% (95% CI, 5.2%-40.3%) in patients with TNBC; 34.8% (95% CI, 16.4%-57.3%) in patients with HR-positive, ERBB2-negative, and DDR-positive BC; and 63.6% (95% CI, 30.8%-89.1%) in patients with platinum-sensitive, BRCA1/2-altered OC. Responses occurred more frequently in patients with BRCA1/2-altered tumors. Durable responses were observed in patients with TNBC (median range DOR, 11.1 3.4-20.4 months); HR-positive, ERBB2-negative, and DDR-positive BC (median range DOR, 15.7 3.9 to ≥20.6 months); and BRCA1/2-altered OC (median DOR not reached; range, 5.6 to ≥18.4 months). The most common grade 3 or greater treatment-related adverse events were anemia (75 patients 33.6%), thrombocytopenia (48 patients 21.5%), and neutropenia (31 patients 13.9%).
This nonrandomized controlled trial found that ORRs for avelumab plus talazoparib were comparable with those with PARP inhibitor or ICI monotherapy. Prolonged DOR in patients with TNBC; HR-positive, ERBB2-negative, and DDR-positive BC; and BRCA1/2-altered OC warrant further investigation in randomized clinical trials. These data highlight the importance of prospective patient selection in future studies of ICI and PARP-inhibitor combinations.
ClinicalTrials.gov Identifier: NCT03330405.
The modern antiquities market uses radiocarbon (14C) dating to screen for forged objects. Although this fact shows the potential and power of the method, the circumstances where it is applied can be ...questionable and call for our attention. Here we present an outline of a call to radiocarbon laboratories for due diligence and best practice approaches to the analysis of antique objects requested by non-research clients.
Neonatal transpyloric feeding (TPF) has not been rigorously studied since the 1980s. Our objective was to evaluate early TPF, defined as TPF initiated within the first week after birth, among preterm ...infants in the setting of modern neonatal practice.
A retrospective cohort study was conducted between 2013 and 2017 for all extremely low birth weight (ELBW) infants born in a tertiary neonatal intensive care unit where early TPF is a common practice. Infants were excluded if they did not receive enteral feeding within the first week after birth or if they died prior to initiation of enteral feeding. The primary outcome was death or bronchopulmonary dysplasia (BPD). The association between early TPF and the primary outcome was assessed using multivariable logistic regression, with adjustment for gestational age, birth weight, and intubation status.
The study sample included 368 ELBW infants. Twenty-seven percent received early TPF. Death or BPD occurred in 58% of infants who received early TPF compared with 67% of infants who received gastric feeding, adjusted odds ratio 0.6, 95% confidence interval 0.3-0.9. Growth and adverse gastrointestinal outcomes did not differ between the two groups.
Early TPF is associated with reduced risk of death or BPD among ELBW infants. Further investigation in the form of a randomized controlled trial is required to confirm a causal association between early TPF and improved clinical outcomes.
The current study examined associations of symptoms of posttraumatic stress disorder PTSD, depression, and generalized anxiety disorder GAD with alcohol consumption and drinking to cope in a sample ...of 310 nurses during the first six months of the COVID-19 pandemic.
Using a cross-sectional design, nurses completed online surveys.
Over 50% of the sample reported alcohol misuse and 12.2% reported drinking to cope. Further, 38.7% reported elevated symptoms of PTSD, 29.7% moderate-to-high symptoms of depression, and 56.8% elevated symptoms of GAD symptoms. Hierarchical regression analyses were conducted to examine how mental health symptoms were associated with alcohol outcomes, controlling for age, gender pronouns, education, and race. No significant predictors emerged for alcohol consumption. Significant associations of symptoms of PTSD and depression were found for drinking to cope, such that higher levels of mental health symptoms were associated with greater endorsement of drinking to cope.
Results are discussed in light of increasing prevention and support services for nurses.
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