Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

Simple Summary This study examined the real-world experience and occurrence of immune-related adverse events (irAEs) under cancer checkpoint immunotherapy, and the relationship between its treatment rechallenge status and their impact on clinical outcomes. The current study demonstrates that immune checkpoint inhibitors (ICI) reinitiation after an irAE-related interruption in the setting of cancer immunotherapy was not associated with significantly improved survival outcome when compared with those without ICI treatment reinitiation after irAE-related therapy interruption. Abstract Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.
Asking People to Explain Complex Policies Does Not Increase Political Moderation: Three Preregistered Failures to Closely Replicate Fernbach, Rogers, Fox, and Sloman’s (2013) Findings

Fernbach et al. (2013) found that political extremism and partisan in-group favoritism can be reduced by asking people to provide mechanistic explanations for complex policies, thus making their lack of procedural-policy knowledge salient. Given the practical importance of these findings, we conducted two preregistered close replications of Fernbach et al.’s Experiment 2 (Replication 1a: N = 306; Replication 1b: N = 405) and preregistered close and conceptual replications of Fernbach et al.’s Experiment 3 (Replication 2: N = 343). None of the key effects were statistically significant, and only one survived a small-telescopes analysis. Although participants reported less policy understanding after providing mechanistic policy explanations, policy-position extremity and in-group favoritism were unaffected. That said, well-established findings that providing justifications for prior beliefs strengthens those beliefs, and well-established findings of in-group favoritism, were replicated. These findings suggest that providing mechanistic explanations increases people’s recognition of their ignorance but is unlikely to increase their political moderation, at least under these conditions.
OTTER, a new method for quantifying absolute amounts of tRNAs

To maintain an optimal proteome, both codon choice of each mRNA and supply of aminoacyl-tRNAs are two principal factors in translation. Recent reports have revealed that the amounts of tRNAs in cells are more dynamic than we had expected. High-throughput methods such as RNA-seq and microarrays are versatile for comprehensive detection of changes in individual tRNA amounts, but they suffer from inability to assess signal production efficiencies of individual tRNA species. Thus, they are not the perfect choice to measure absolute amounts of tRNAs. Here, we introduce a novel method for this purpose, termed oligonucleotide-directed three-prime terminal extension of RNA (OTTER), which uses fluorescence-labeling at the 3′ terminus of a tRNA by optimized reverse primer extension and an assessment step of each labeling efficiency by northern blotting. Using this method, we quantified the absolute amounts of the 34 individual and four pairs of isoacceptor tRNAs out of the total 42 nuclear-encoded isoacceptors in the yeast Saccharomyces cerevisiae. We found that the amounts of tRNAs in log phase yeast cells grown in a rich glucose medium range from 0.030 to 0.73 pmol/µg RNA. The tRNA amounts seem to be altered at the isoacceptor level by a few folds in response to physiological growing conditions. The data obtained by OTTER are poorly correlated with those by simple RNA-seq, marginally with those by microarrays and by microscale thermophoresis. However, the OTTER data showed good agreement with the data obtained by 2D-gel analysis of in vivo radiolabeled RNAs. Thus, OTTER is a suitable method for quantifying absolute amounts of tRNAs at the level of isoacceptor resolution.
Supplemental Intraoperative Oxygen and Long-term Mortality: Subanalysis of a Multiple Crossover Cluster Trial

Background: Whether supplemental oxygen worsens long-term mortality remains unclear, with contradictory trial results. The authors therefore tested the hypothesis that supplemental oxygen (80% vs. 30%) increases the hazard for long-term mortality. Methods: The authors conducted a post hoc analysis of a large multiple crossover cluster trial in which more than 5,000 colorectal surgeries on 4,088 adults were allocated to receive either 30% or 80% inspired oxygen during general anesthesia. The authors assessed the effect of 80% versus 30% target-inspired oxygen on long-term mortality and calculated Kaplan–Meier survival estimates. Analysis was restricted to patients with a home address in Ohio because the authors could obtain reliable vital status information from the Ohio Department of Health (Columbus, Ohio) for them. Results: A total of 3,471 qualifying colorectal surgeries performed in 2,801 patients were analyzed, including 1,753 (51%) surgeries in 1,577 patients given 80% oxygen and 1,718 surgeries in 1,551 patients given 30% oxygen. The observed incidence of death after a median of 3 yr was 13% (234 of 1,753) in the 80% oxygen group and 14% (245 of 1,718) in the 30% oxygen group. The estimated hazard ratio for mortality was 0.94 (95% CI, 0.78 to 1.13; P = 0.493). Conclusions: In this post hoc analysis of a large, controlled trial, supplemental oxygen did not increase postoperative mortality. In a post hoc analysis of a controlled trial of 3,471 colorectal surgeries, the incidence of death after a median of 3 yr of follow-up was 13% with 80% oxygen and 14% with 30% oxygen, giving an estimated hazard ratio for mortality of 0.94 (95% CI, 0.78 to 1.13; P = 0.493). Supplemental oxygen does not increase mortality.
Is there an association between long-term antibiotics for acne and subsequent infection sequelae and antimicrobial resistance? A systematic review

Background Antimicrobial resistance (AMR) is a global health priority. Acne vulgaris is a common skin condition for which antibiotic use ranges from a few months to years of daily exposure. Aim To systemically search for and synthesise evidence on the risk of treatment-resistant infections, and other evidence of AMR, following long-term oral antibiotic use for acne. Design & setting In this systematic review, a literature search was carried out using the databases Embase, MEDLINE, Cochrane, and Web of Science. They were searched using MeSH, Emtree, or other relevant terms, and followed a pre-registered protocol. Method Search strategies were developed with a librarian and undertaken in July 2019. All searches date from database inception. The primary outcome was antibiotic treatment failure or infection caused by a resistant organism. Secondary outcomes included detection of resistant organisms without an infection, rate of infection, or changes to flora. Results A total of 6996 records were identified. Seventy-three full-text articles were shortlisted for full review, of which five were included. Two investigated rates of infection, and three resistance or changes to microbial flora. Three studies had 35 or fewer participants (range 20–118 496). Three studies had a serious or high risk of bias, one moderate, and one a low risk of bias. Weak evidence was found for an association between antibiotic use for acne and subsequent increased rates of upper respiratory tract infections and pharyngitis. Conclusion There is a lack of high quality evidence on the relationship between oral antibiotics for acne treatment and subsequent AMR sequelae. This needs to be urgently addressed with rigorously conducted studies.
Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies

Simple Summary Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play instrumental roles in carcinogenesis. However, the genetic alterations of the STAT3/CDK2/4/6 signaling axis and its role in predicting immune infiltration and immunotherapeutic response remain unclear. Here, we used in silico analyses of multi-Omics data to map out the role of epigenetic and genetic alterations of STAT3/CDK2/4/6 in tumor immune infiltrations, immunotherapy response, and prognosis of cancer patients. Our study collectively suggested that STAT3/CDK2/4/6 are important onco-immune signatures that contribute to tumor immune invasion, poor prognoses, and immune therapy failure. Our finding may be clinically useful in designing therapeutic strategies, prognosis assessment, and follow-up management in patients receiving immunotherapy in multiple cancers. Abstract Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it’s associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy.
Microbial Communities of Meat and Meat Products: An Exploratory Analysis of the Product Quality and Safety at Selected Enterprises in South Africa

Consumption of food that is contaminated by microorganisms, chemicals, and toxins may lead to significant morbidity and mortality, which has negative socioeconomic and public health implications. Monitoring and surveillance of microbial diversity along the food value chain is a key component for hazard identification and evaluation of potential pathogen risks from farm to the consumer. The aim of this study was to determine the microbial diversity in meat and meat products from different enterprises and meat types in South Africa. Samples (n = 2017) were analyzed for Yersinia enterocolitica, Salmonella species, Listeria monocytogenes, Campylobacter jejuni, Campylobacter coli, Staphylococcus aureus, Clostridium perfringens, Bacillus cereus, and Clostridium botulinum using culture-based methods. PCR was used for confirmation of selected pathogens. Of the 2017 samples analyzed, microbial ecology was assessed for selected subsamples where next generation sequencing had been conducted, followed by the application of computational methods to reconstruct individual genomes from the respective sample (metagenomics). With the exception of Clostridium botulinum, selective culture-dependent methods revealed that samples were contaminated with at least one of the tested foodborne pathogens. The data from metagenomics analysis revealed the presence of diverse bacteria, viruses, and fungi. The analyses provide evidence of diverse and highly variable microbial communities in products of animal origin, which is important for food safety, food labeling, biosecurity, and shelf life limiting spoilage by microorganisms.
Relationship Between Phase Contrast Microscopy and Transmission Electron Microscopy Results of Samples from Occupational Exposure to Airborne Chrysotile Asbestos

Transmission electron microscope (TEM) and phase contrast microscope (PCM) fiber counts from the same filter were compared. Industrial hygiene samples from operations within a chrysotile mine, crusher, mill and tailings site, a brake manufacturing industry, and a taping products manufacturer were used. A total of 10 318 individual fibers were analyzed from 65 filter samples. The aim of the study was to derive the relationships between TEM counts and PCM counts that could be used in the extrapolation of risk estimate from occupational exposure to low-level nonoccupational exposure to asbestos. The results show that ratios of EM-PCM equivalent to PCM counts vary between 1.4 to 3.2. The proportion of long thin fibers (L>8 µm, D<1.5 µm) increased as the asbestos operation moved from primary sector (mining) to end use sector (manufacturing).
Determinants of Travel Participation and Experiences of Wheelchair Users Traveling to the Bodrum Region: A Qualitative Study

Although the number of people with disabilities and types of disability increases day by day, a sufficient point has not been reached regarding accessible tourism. The participation rate of people with disabilities (PWDS) in tourism activities is low, and there is a big gap in the travel and accommodation sector in this regard. Studies of previous scholars have concluded that the accessible tourism market is a significant and profitable area, but determinants of participation to travel and process of travel, such as wheelchair user expectations, are consistently ignored by the tourism industry. The main purpose of this study is to determine the determinants of travel by examining the motivations, expectations, processes and experiences of PWDS using wheelchairs to participate in tourism. Research was performed in Turkey’s Bodrum district; 25 wheelchair users were included in the study. The keywords that emerged in the theoretical framework in light of the answers given to 39 open-ended questions online were coded in the Nvivo program. The results showed that wheelchair users intended to go on vacation but were less motivated to participate due to the lack of travel conditions. Wheelchair travelers argued that a companion was required for an enjoyable holiday that could meet their needs. In addition, the results revealed that the types of wheelchairs used by disabled passengers differ. The disabled stated that the wheelchairs they use in daily life are not suitable for use on the beach, sand or water. Despite the economic, social and technological change opportunities, basic tourism service expectations of PWDS are not met. This research project is a comprehensive study that makes determinations in terms of examining the social status of disabled people in terms of social sciences, examining the place and importance of disabled tourists in the market and eliminating the deficiencies of facilities serving in tourism.
Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random

Supplemental Digital Content is available in the text. Background. The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. Methods. We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than −3 mL/min/y; stable renal function: −3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. Results. Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. Conclusions. Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.
Can Serendipity Still Hold Any Surprises in the Coordination Chemistry of Mixed-Donor Macrocyclic ligands? The Case Study of Pyridine-Containing 12-Membered Macrocycles and Platinum Group Metal ions PdII, PtII, and RhIII

This study investigates the coordination chemistry of the tetradentate pyridine-containing 12-membered macrocycles L1-L3 towards Platinum Group metal ions PdII, PtII, and RhIII. The reactions between the chloride salts of these metal ions and the three ligands in MeCN/H2O or MeOH/H2O (1:1 v/v) are shown, and the isolated solid compounds are characterized, where possible, by mass spectroscopy and 1H- and 13C-NMR spectroscopic measurements. Structural characterization of the 1:1 metal-to-ligand complexes [Pd(L1)Cl]2[Pd2Cl6], [Pt(L1)Cl](BF4), [Rh(L1)Cl2](PF6), and [Rh(L3)Cl2](BF4)·MeCN shows the coordinated macrocyclic ligands adopting a folded conformation, and occupying four coordination sites of a distorted square-based pyramidal and octahedral coordination environment for the PdII/PtII, and RhIII complexes, respectively. The remaining coordination site(s) are occupied by chlorido ligands. The reaction of L3 with PtCl2 in MeCN/H2O gave by serendipity the complex [Pt(L3)(μ-1,3-MeCONH)PtCl(MeCN)](BF4)2·H2O, in which two metal centers are bridged by an amidate ligand at a Pt1-Pt2 distance of 2.5798(3) Å and feature one square-planar and one octahedral coordination environment. Density Functional Theory (DFT) calculations, which utilize the broken symmetry approach (DFT-BS), indicate a singlet d8-d8 PtII-PtII ground-state nature for this compound, rather than the alleged d9-d7 PtI-PtIII mixed-valence character reported for related dinuclear Pt-complexes.
N‐acylethanolamine‐hydrolysing acid amidase: A new potential target to treat paclitaxel‐induced neuropathy

Although paclitaxel is an effective chemotherapeutic agent used to treat multiple types of cancer (e.g. breast, ovarian, neck and lung), it also elicits paclitaxel‐induced peripheral neuropathy (PIPN), which represents a major dose‐limiting side effect of this drug.
Molecular Docking Studies and Biological Evaluation of Berberine–Benzothiazole Derivatives as an Anti-Influenza Agent via Blocking of Neuraminidase

In this study, we have introduced newly synthesized substituted benzothiazole based berberine derivatives that have been analyzed for their in vitro and in silico biological properties. The activity towards various kinds of influenza virus strains by employing the cytopathic effect (CPE) and sulforhodamine B (SRB) assay. Several berberine–benzothiazole derivatives (BBDs), such as BBD1, BBD3, BBD4, BBD5, BBD7, and BBD11, demonstrated interesting anti-influenza virus activity on influenza A viruses (A/PR/8/34, A/Vic/3/75) and influenza B viral (B/Lee/40, and B/Maryland/1/59) strain, respectively. Furthermore, by testing neuraminidase activity (NA) with the neuraminidase assay kit, it was identified that BBD7 has potent neuraminidase activity. The molecular docking analysis further suggests that the BBD1–BBD14 compounds’ antiviral activity may be because of interaction with residues of NA, and the same as in oseltamivir.
The Biochemistry of Phytocannabinoids and Metabolic Engineering of Their Production in Heterologous Systems

The medicinal properties of cannabis and the its legal status in several countries and jurisdictions has spurred the massive growth of the cannabis economy around the globe. The value of cannabis stems from its euphoric activity offered by the unique phytocannabinoid tetrahydrocannabinol (THC). However, this is rapidly expanding beyond THC owing to other non-psychoactive phytocannabinoids with new bioactivities that will contribute to their development into clinically useful drugs. The discovery of the biosynthesis of major phytocannabinoids has allowed the exploration of their heterologous production by synthetic biology, which may lead to the industrial production of rare phytocannabinoids or novel synthetic cannabinoid pharmaceuticals that are not easily offered by cannabis plants. This review summarizes the biosynthesis of major phytocannabinoids in detail, the most recent development of their metabolic engineering in various systems, and the engineering approaches and strategies used to increase the yield.
A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction‐Mediated Cancer Therapy

Subcellular organelle‐targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off‐target side effects. Herein, a multichannel calcium ion (Ca2+) nanomodulator (CaNMCUR+CDDP), i.e., a cisplatin (CDDP) and curcumin (CUR) co‐incorporating calcium carbonate (CaCO3) nanoparticle, is prepared by a facile one‐pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+‐overload‐induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEGCaNMCUR+CDDP) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria‐targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging‐guided organelle‐targeted cancer therapy in the future.