bluuebunny/crossref_metadata_2025 huggingface dataset:
A Qualitative Exploration of Stakeholders’ Preferences for Early-Stage Rectal Cancer Treatment
Authors: Rubens Merrill E. , Mayo Timothy P. , Smith Radhika K. , Glasgow Sean C. , Politi Mary C.
Published: December 2023

As treatment options for patients with rectal cancer evolve, patients with early-stage rectal cancer may have a treatment choice between surgery and a trial of nonoperative management. Patients must consider the treatments’ clinical tradeoffs alongside their personal goals and preferences. Shared decision-making (SDM) between patients and clinicians can improve decision quality when patients are faced with preference-sensitive care options. We interviewed 28 stakeholders (13 clinicians and 15 patients) to understand their perspectives on early-stage rectal cancer treatment decision-making. Clinicians included surgeons, medical oncologists, and radiation oncologists who treat rectal cancer. Adult patients included those diagnosed with early-stage rectal cancer in the past 5 years, recruited from an institutional database. A semi-structured interview guide was developed based on a well-established decision support framework and reviewed by the research team and stakeholders. Interviews were conducted between January 2022 and January 2023. Transcripts were coded by 2 raters and analyzed using thematic analysis. Both clinicians and patients recognized the importance of SDM to support high-quality decisions about the treatment of early-stage rectal cancer. Barriers to SDM included variable clinician motivation due to lack of training or perception of patients’ desires or abilities to engage, as well as time-constrained encounters. A decision aid could help facilitate SDM for early-stage rectal cancer by providing standardized, evidence-based information about treatment options that align with clinicians’ and patients’ decision needs.
Hypoxia activates the hypoxia-inducible factor-1α/vascular endothelial growth factor pathway in a prostatic stromal cell line: A mechanism for the pathogenesis of benign prostatic hyperplasia
Authors: Zhang Tao , Mao Changlin , Chang Yao , Lyu Jiaju , Zhao Delong , Ding Sentai
Published: December 2023

Background

The development of benign prostatic hyperplasia (BPH) is closely related to hypoxia in the prostatic stroma, and the hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway has been shown to significantly activate in response to hypoxia. The underlying mechanism for activation of this pathway in the pathogenesis of BPH remains unclear.

Materials and methods

We constructed HIF-1α overexpression and knockdown BPH stromal (WPMY-1) and epithelial (BPH-1) cell lines, which were cultured under different oxygen conditions (hypoxia, normoxia, and hypoxia + HIF-1α inhibitor). Quantitative real-time polymerase chain reaction (qPCR) and Western blotting were applied to detect the expression of the HIF-1α/VEGF pathway. Cell proliferation and apoptosis were analyzed by Cell Counting Kit-8 and flow cytometry. We used the miRWalk 2.0 database and Western blotting to predict the potential miRNA that selectively targets the HIF-1α/VEGF pathway, and verified the prediction by qPCR and dual-luciferase assays.

Results

In a BPH stromal cell line (WPMY-1), the expression of VEGF was in accordance with HIF-1α levels, elevated in the overexpression cells and decreased in the knockdown cells. Hypoxia-induced HIF-1α overexpression, which could be reversed by a HIF-1α inhibitor. Moreover, the HIF-1α inhibitor significantly depressed cellular proliferation and promoted apoptosis in hypoxic conditions, assessed by Cell Counting Kit-8 and flow cytometry. However, in the BPH epithelial cell line (BPH-1), the expression level of HIF-1α did not influence the expression of VEGF. Finally, a potential miRNA, miR-17-5p, regulating the HIF-1α/VEGF pathway was predicted from the miRWalk 2.0 database and Western blotting, and verified by qPCR and dual-luciferase assay.

Conclusions

In hypoxia, activation of the HIF-1α/VEGF pathway plays a crucial role in regulating cell proliferation in a BPH stromal cell line. Regulation by miR-17-5p may be the potential mechanism for the activation of this pathway. Regulation of this pathway may be involved in the pathogenesis of BPH.
A comparison of the continuous supraclavicular brachial plexus block using the proximal longitudinal oblique approach and the interscalene brachial plexus block for arthroscopic shoulder surgery
Authors: Kim Yeon Ju , Kim Hyungtae , Kim Sehee , Kang Mi-Ra , Kim Ha-Jung , Koh Won Uk , Lee Sooho , Ro Young-Jin
Published: December 2023

BACKGROUND

Continuous interscalene brachial plexus block (ISB) is widely used for arthroscopic shoulder surgery, but the incidence of hemidiaphragmatic paresis (HDP) has been reported to reach 100%. Several methods, including injections distal to the C5–C6 nerve roots, have been attempted to reduce the HDP incidence. However, catheter placement distal to the C5–C6 nerve roots interferes with the surgical site.

OBJECTIVE

Our primary objective was to describe a new technique, the supraclavicular brachial plexus block (SCB), using the proximal longitudinal oblique approach (PLO-SCB), which can facilitate catheter placement and, when compared with ISB, to test whether this would provide noninferior analgesia and spare the phrenic nerve.

DESIGN

Prospective, randomised, double-blind study.

SETTING

Operating rooms, postanaesthesia care unit, and wards.

PATIENTS

Seventy-six patients aged 20 to 80 years scheduled for arthroscopic shoulder surgery.

INTERVENTIONS

Patients were randomly assigned to the continuous PLO-SCB (n = 40) or the continuous ISB (n = 40) groups. All patients received an initial low-volume single-injection (5 ml 0.75% ropivacaine) followed by a patient-controlled infusion of 0.15% ropivacaine.

MAIN OUTCOME MEASURES

The primary outcomes were the incidence of HDP and pain scores. Secondary outcomes were respiratory function, postoperative analgesic consumption, sensory and motor function, and complications.

RESULTS

The HDP incidence was significantly lower in the PLO-SCB group than in the ISB group at 30 min after block injection: 0% (0 of 38 patients) and 73.7% (28 of 38 patients), respectively (P < 0.001). Similarly, at 24 h after surgery, the incidences were 23.7% (9 of 38 patients) and 47.4% (18 of 38 patients) in the PLO-SCB and ISB groups, respectively (P = 0.002). Median [IQR] NRS pain scores at rest measured after surgery in the ISB and PLO-SCB groups were similar: immediately after surgery, 1 [0 to 2] vs. 1 [0 to 1], P = 0.06); at 30 min, 2 [0.25 to 2] vs. 1 [0 to 2], P = 0.065); and at 24 h 2 [0.25 to 3] vs. 1 [0 to 3], P = 0.47, respectively.

CONCLUSION

For major shoulder surgery, compared with continuous ISB, continuous PLO-SCB was more sparing of diaphragmatic and respiratory function while providing noninferior analgesia. Catheter placement via the PLO approach is feasible without interfering with the surgical field.

TRIAL REGISTRATION

Registered by the Clinical Trial Registry of Korea (Seoul, Korea; KCT0004759, http: cris.nih.go.kr, principal investigator: Hyungtae Kim).
Flap Survival after Reconstructive Surgery for Pressure Ulcers: A Cohort Study
Authors: Nööjd Mari , Wyckman Alexander , Steinvall Ingrid , Elmasry Moustafa
Published: December 2023

Background:

Pressure ulcers are troublesome for patients and require considerable resources to resolve. Previous studies have focused on recurrence, whereas there are few studies on flap survival. The aim was to describe the group and to analyze possible factors for flap survival.

Method:

A descriptive retrospective analysis of all operations between 2008 and 2020 was carried out. Flap survival at 40 days was assessed. A flap was classified as a failure if a reoperation with removal or replacement was planned before, or in connection with, the first return visit. Variables of patient demographics, details of the pressure ulcers, and surgical treatment and care were analyzed with multivariable logistic regression for their effect on flap survival.

Results:

A total of 111 flaps were included [78 (70%) with random blood supply and 33 (30%) with axial or perforator-based blood supply]; 54 (49%) of the flaps were fasciocutaneous. Body mass index was 25 (IQR 22–28). Flap survival rate was 90%. Variables associated with flap failure were higher body mass index, congenital spinal cord injury, type of blood supply to the flap, and the use of methylene blue to guide debridement of the wound.

Conclusions:

The findings show factors that can be modified to improve future results, including a normalized body mass index and use of methylene blue in surgery to outline wound edges and depth, as this has been shown to protect against flap failure. Our data suggest that random flaps, such as V-Y, are preferable to axial flaps in the studied group.
Analysis of Medical Device Reports That Contributed to a Class I Recall
Authors: Shirazyan Anna
Published: December 2023

The Food and Drug Administration (FDA) conducts postmarket review of medical devices as a part of its mission to protect patient safety and ensure product safety and effectiveness. Medical device reports (MDRs) are one way the FDA receives information on adverse events involving medical devices. Medical device reports can be submitted by manufacturers, importers, user facilities, and the public. User facilities are required to report device-related adverse events that resulted in a serious injury or death. In addition, user facilities are encouraged to submit voluntary medical reports where a device problem has the potential for patient harm. The FDA receives MDRs from user facilities through the MedWatch and Medical Product Safety Network programs. When reporters include detailed background information in their reports, they can directly contribute to meaningful action. Health technology management personnel, including clinical engineers, have unique insights into medical device problems and can provide valuable background information in MDRs. The highlighted examples hereinafter illustrate 2 cases where more detailed information included in MDRs was essential and contributed to a class I recall of a medical device.
Methodology for the Evaluation and Selection of High-Complexity Medical Equipment
Authors: Marolla Ignacio M.
Published: December 2023

Given the need to acquire magnetic resonance imaging equipment through public tender, and to objectify the decision-making process, which takes into account multiple variables, a mathematical model has been developed based on the use of the analytic hierarchy process multicriteria analysis method, the linear weighting method, and the use of indicators to compare offers. For this purpose, a hierarchy of evaluating criteria to aid in selection processes has been defined and compared by a multidisciplinary team consisting of engineers, medical imaging specialists, lawyers, and economists who collaboratively developed and obtained a criteria prioritization scheme. Within this scheme, suppliers' offers were evaluated through indicators and then weighted accordingly to obtain a numerical ranking. The method has turned out to be applicable in evaluating and selecting highly complex biomedical technology and provides a hierarchical ranking of offers based on a numerical priority that considers multiple criteria. In the fast-growing market of medical technology, this method improves evaluative processes that depend on multiple criteria and helps institutions reduce risk when making decisions.
Preoperative systemic inflammation response index: Clinicopathologic predictor of pathological complete response in HER2-positive breast cancer patients receiving neoadjuvant systemic therapy
Authors: Wu Hong-Yu , Lin Chin-Yao , Tzeng Yen-Dun , Hung Chih-Chiang , Liu Shiuh-Inn , Yin Chun-Hao , Chen Jin-Shuen , Chen Yao-Shen , Yang Jie-Ru
Published: December 2023

Background:

Multiple pretreatment systemic inflammatory markers (SIMs) have been reported as predictors of pathological complete response (pCR) after neoadjuvant systemic therapy (NST) in patients with breast cancer (BC). However, the most significant SIM remains to be conclusively identified, and variations among different molecular subtypes remain unknown. The objective of the study was to identify the most significant SIM in patients with human epidermal growth factor receptor 2 (HER2) positive BC, to construct a pCR-predictive nomogram combining it with other clinicopathologic factors, and to evaluate its prognostic value on survival.

Methods:

We retrospectively reviewed the findings for 240 patients with stage I-III HER2-positive BC who underwent NST and subsequent surgery at Kaohsiung and Taichung Veterans General Hospital from 2011 to 2021. Clinicopathologic factors were analyzed by stepwise logistic regression with backward selection. The data were used to construct a nomogram plot for determining the pCR probability. Kaplan-Meier curves and log-rank test were used to evaluate disease-free survival (DFS) and overall survival (OS).

Results:

Among the pretreatment SIMs, only the systemic inflammation response index (SIRI) was significantly related to pCR, with an optimal cutoff value of 1.27 × 109/L. Stepwise logistic analyses indicated that clinical N stage, HER2 immunohistochemistry score, hormone receptor status, targeted therapy regimen, and SIRI were independent predictors of pCR, with an area under the curve of 0.722. The Hosmer-Lemeshow test and calibration curve revealed that the predictive ability was a good fit to actual observations. A nomogram was constructed based on the logistic model. The external validation of the model also revealed satisfactory discrimination and calibration. Kaplan-Meier analysis showed that patients with SIRI <1.27 had longer DFS and OS.

Conclusion:

Pretreatment SIRI <1.27 is predictive of pCR, DFS, and OS in HER2-positive BC. Our nomogram could efficiently predict pCR and facilitate clinical decision-making before neoadjuvant treatment.
Performance status as a prognostic surrogate in hepatocellular carcinoma: Role of albumin–bilirubin and easy-albumin–bilirubin grade
Authors: Liao Jia-I , Ho Shu-Yein , Hou Ming-Chih , Liu Po-Hong , Hsu Chia-Yang , Huo Teh-Ia
Published: December 2023

Background:

Performance status (PS) is associated with the severity of liver cirrhosis and is also an important survival determinant in hepatocellular carcinoma (HCC). Albumin–bilirubin (ALBI) grade and easy (EZ)-ALBI grade have been proposed to evaluate liver dysfunction in HCC, but their role in patients with different PS is unclear. We aimed to investigate the prognostic role of ALBI and EZ-ALBI grade in a large HCC cohort with variable PS.

Methods:

A total of 3355 newly diagnosed HCC patients between 2002 and 2018 were identified and retrospectively analyzed. Independent prognostic predictors associated with survival were investigated using the Cox proportional hazards model.

Results:

Patients with poor PS had decreased survival compared with those with good PS. In the Cox model, creatinine ≥1.2 mg/dL, α-fetoprotein (AFP) ≥20 ng/mL, vascular invasion, distant metastasis, total tumor volume >100 cm3, presence of ascites, ALBI grades 2 and 3, EZ-ALBI grade 2 and grade 3, PS 1–4, and noncurative treatment were independently associated with higher mortality in the entire cohort (all p < 0.001). ALBI grade and EZ-ALBI grade can well stratify overall survival in subgroup patients with PS 0, PS 1–2, and PS 3–4 (all p < 0.001).

Conclusion:

Patients with good PS have better long-term survival compared with those with poor PS. ALBI and EZ-ALBI grade can discriminate long-term outcome in the entire cohort as well as in patients with different PS. ALBI and EZ-ALBI are objective and feasible prognostic models to evaluate liver dysfunction in HCC patients independent of PS.
The effect of radiotherapy on patients with pathological stage IIB breast cancer after breast-conserving surgery or mastectomy: A cohort study
Authors: Pan Yi-Ying , Lai Tzu-Yu , Shiau Cheng-Ying , Tseng Ling-Ming , Lai I-Chun , Liu Yu-Ming , Huang Pin-I
Published: December 2023

Background:

Breast cancer is one of the most common cancers in women, and treatment options include surgery, systemic therapies, and radiotherapy (RT). While postoperative RT plays an important role in reducing local recurrence rates and improving survival outcomes, its exact impact on patients with pathological stage IIB breast cancers remains unidentified.

Methods:

In this retrospective cohort study, patients with newly diagnosed pathological stage IIB breast cancer who underwent surgery and postoperative RT were included. The data were collected from medical records, and survival outcomes were assessed using the Kaplan-Meier method, log-rank tests, and Cox regression models.

Results:

In total, 350 patients participated in this study. Overall survival, locoregional recurrence-free survival, event-free survival, and distant metastasis-free survival rates did not significantly differ between those who received RT and those who did not. Multivariate analyses revealed that patients who received anthracycline or taxane chemotherapy had better survival outcomes.

Conclusion:

Our findings demonstrated that postoperative RT had no significant effect on overall survival, locoregional recurrence, event-free survival, or distant metastasis rates in patients with pathological stage IIB breast cancer. However, anthracycline- and taxane-based chemotherapies were associated with improved outcomes. These findings demonstrated the complexities of treating such patient populations with multimodal therapies. Further research is needed to ensure optimal postoperative RT in patients with pathological stage IIB breast cancer. Clinicians must consider individual patient characteristics and incorporate comprehensive treatment approaches to ensure successful outcomes in this population.
Long-term oncological outcomes of transanal versus laparoscopic total mesorectal excision for mid-low rectal cancer: a retrospective analysis of 2502 patients
Authors: Li Ze , Liu Huashan , Luo Shuangling , Hou Yujie , Zhou Yebohao , Zheng Xiaobin , Zhang Xingwei , Huang Liang , Zeng Ziwei , Kang Liang
Published: December 2023

Background:

Transanal total mesorectal resection (taTME) has recently emerged as a promising surgical approach for the treatment of mid-low rectal cancer. However, there is limited evidence on the long-term survival outcomes associated with taTME. This retrospective study aimed to compare the overall survival (OS), disease-free survival (DFS), and cancer-specific survival of taTME and laparoscopic TME (laTME) in patients with mid-low rectal cancer.

Materials and Methods:

From July 2014 to June 2022, a total of 3627 patients were identified from two prospective cohorts: the laparoscopic rectal surgery cohort and the CNTAES cohort. To balance the baseline characteristics between the taTME and laTME groups, propensity score matching (PSM) was performed.

Results:

A total of 2502 patients were included in the study. Prior to PSM, the laTME group comprised 1853 patients, while the taTME group comprised 649 patients. The 5-year OS (82.9% vs. 80.4%, P=0.202) and 5-year DFS (74.4% vs. 72.5%, P=0.167) were comparable between the taTME and laTME groups. After PSM, the taTME group showed no statistically significant difference in the 5-year OS (83.1% vs. 79.2%, P=0.101) and 5-year DFS (74.8% vs. 72.1%, P=0.135) compared to the laTME group. Subgroup analysis further suggested that taTME may potentially reduce the risk of death [hazard ratio 0.652; (95% CI, 0.452–0.939)] and disease recurrence [hazard ratio 0.736; (95% CI, 0.562–0.965)] specifically in patients with low rectal cancer.

Conclusion:

In this study, taTME demonstrated comparable oncologic safety to laTME in patients with mid-low rectal cancer. Moreover, the results indicate that taTME may confer potential survival benefits for patients with low rectal cancer.
Advance Care Planning Engagement Strategies for Primary Care Providers Seeing Diverse Patient Populations
Authors: Kirkpatrick Haley , Buccheri Robin K. , Sharifi Claire
Published: December 2023

Diverse patients are less likely than Whites to have advance care planning. The primary purpose of this scoping review was to summarize recent evidence about advance care planning engagement interventions for primary care providers working with diverse patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses-extension for Scoping Reviews (PRISMA-ScR) Checklist was followed. Peer-reviewed articles published in English since 2000 reporting the results of studies testing intervention programs in primary care to improve advance care planning with adult, racially diverse populations were included. Searches were conducted in 5 online databases and yielded 72 articles. Gray literature yielded 23 articles. Two authors independently reviewed the abstracts of 72 articles determining that 9 articles met the aim of this review. These studies were analyzed by communication tools and other resources, population, intervention, primary outcomes, instruments, and primary findings and organized into 3 categories: (a) provider-focused interventions, (b) patient-focused interventions, and (c) multilevel interventions. Improvement in advance care planning outcomes can be achieved for racially diverse populations by implementing targeted advance care planning engagement interventions for both providers and patients. These interventions can be used in primary care to increase advance care planning for diverse patients. More research is needed that evaluates best practices for integrating advance care planning into primary care workflows.
Development of therapeutic cancer vaccines using nanomicellar preparations
Authors: Qin Yan , Zeng Wen-Feng , Liang Wei
Published: December 2023

Cancer treatment is a multifaceted challenge, and therapeutic vaccines have emerged as a promising approach. The micellar preparation efficiently encapsulates antigen polypeptides and enhances antigen presentation through the major histocompatibility class I pathway, promoting cytotoxic T lymphocyte immune responses. Moreover, it enables codelivery of both antigen and adjuvant to the same target antigen-presenting cells. Combining the micellar vaccine with traditional cancer treatments (such as chemotherapy, radiotherapy, and surgery) has demonstrated improved efficacy in murine tumor models. Overall, the polyethylene glycol–phosphatidylethanolamine micelle-based vaccine presents a promising platform for cancer therapeutic vaccines. By leveraging the strengths of various treatment modalities, this innovative vaccine approach holds the potential to revolutionize cancer therapy and bring new possibilities for cancer patients.
Endonasal Endoscopic Optic Canal Decompression for Nontraumatic Optic Neuropathy: Long-Term Visual Outcomes in 36 Patients
Authors: Manet Romain , Calvanese Francesco , Jannelli Gianpaolo , Delaidelli Alberto , Fricker Jules , Verrecchia Sarah , Froment Tilikete Caroline , Jouanneau Emmanuel
Published: December 2023

Background:

The management of compressive optic neuropathy (CON) arising from nontraumatic compression of the optic nerve within the optic canal (OC) remains a topic of controversy. In this study, our aim was to assess the effectiveness and safety of endonasal endoscopic optic nerve decompression (EEOND). In addition, we conducted an analysis of prognostic factors that could potentially influence visual outcomes.

Methods:

This retrospective cohort study was conducted between January 2015 and December 2021, involving adult patients (age > 18) diagnosed with CON and treated with EEOND at our specialized skull base expert center. The study evaluated the impact of surgery on visual acuity (VA), mean deficit (MD), and foveal threshold (FT) of the visual field (VF). These parameters were assessed preoperatively and at 3- and 12-month postoperative follow-ups. The relationship between clinical variables and the differences in postoperative to preoperative VA, MD, and FT of the visual field was analyzed through univariate and multivariate approaches.

Results:

Thirty-six patients (38 eyes) were included, with a mean age of 52 (±12) years, and a female predominance (78%). The mean ophthalmologic follow-up duration was 38 (±32) months. At the 12-month follow-up, 39% of the patients exhibited a VA improvement of ≥0.2 LogMAR. Partial VF improvement (MD improvement ≥25%) was observed in 55% of the patients, whereas 19% experienced complete recovery. In multivariate analysis, the presence of a type 4 OC was identified as the sole negative prognostic factor for visual improvement (VA and VF) at 12 months. Six patients (17%) encountered minor surgical complications, all of which were managed conservatively and had no impact on visual outcomes.

Conclusions:

Our study demonstrates that EEOND is a safe and effective procedure, even in cases of severe and long-lasting CON caused by nontraumatic compression of the optic nerve at the level of the OC.
Sleep Duration and Long-Term Mortality After Stroke: A Nationwide Analysis
Authors: Hassani Sara , Ovbiagele Bruce , Markovic Daniela , Towfighi Amytis
Published: December 2023

Background

Sleep duration is a key marker of ideal cardiovascular health in the American Heart Association’s new Life’s Essential 8 construct, but studies on outcomes in stroke survivors are scarce. We assessed the association between sleep duration and mortality among self-reported stroke survivors in a nationally representative U.S. sample.

Methods

Cross-sectional data (2005–2018) from the National Health and Nutrition Examination Surveys database in patients aged ≥18 (n=42,143) with a self-reported history of stroke (n=1,488) were linked to the 2019 National Death Index to determine the association between nightly sleep duration and mortality. Relationships between sleep duration (short: <7 hours, normal: 7-8 hours, long: >8 hours) and demographic characteristics were assessed. Relationships between sleep duration and mortality (all-cause and cardiovascular causes) were evaluated adjusting for demographic and clinical variables, with multivariable Cox regressions.

Results

Among stroke survivors, prevalence of short sleep duration increased with younger age while prevalence of long sleep duration increased with older age (p<0.001). There were no significant sex differences in sleep duration. Long sleep duration was associated with higher all-cause mortality in the unadjusted model (HR 1.82, 1.44-2.31, p<0.0001). After adjustment for co-variates, (HR 1.36, 1.08-1.71, p=0.01), the association attenuated, but remained significant (HR 1.30, 1.02-1.65, p=0.03). Sensitivity analysis further verified the reliability of this conclusion. Short sleep duration was not associated with all-cause or cardiovascular mortality after adjusted analyses. There were no significant associations between long sleep duration and cardiovascular mortality.

Conclusion

Long sleep duration is independently associated with higher risk, all-cause mortality after stroke.
Human genetic evidence enriched for side effects of approved drugs
Authors: Minikel Eric Vallabh , Nelson Matthew R.
Published: December 2023

Safety failures are an important factor in low drug development success rates. Human genetic evidence can select drug targets causal in disease and enrich for successful programs. Here, we sought to determine whether human genetic evidence can also enrich for labeled side effects (SEs) of approved drugs. We combined the SIDER database of SEs with human genetic evidence from genome-wide association studies, Mendelian disease, and somatic mutations. SEs were 2.0 times more likely to occur for drugs whose target possessed human genetic evidence for a trait similar to the SE. Enrichment was highest when the trait and SE were most similar to each other, and was robust to removing drugs where the approved indication was also similar to the SE. The enrichment of genetic evidence was greatest for SEs that were more drug specific, affected more people, and were more severe. There was significant heterogeneity among disease areas the SEs mapped to, with the highest positive predictive value for cardiovascular SEs. This supports the integration of human genetic evidence early in the drug discovery process to identify potential SE risks to be monitored or mitigated in the course of drug development.
Identification of an allele-specific transcription factor binding interaction that regulatesPLA2G2Agene expression
Authors: Hara Aki , Lu Eric , Johnstone Laurel , Wei Michelle , Sun Shudong , Hallmark Brian , Watkins Joseph C. , Zhang Hao Helen , Yao Guang , Chilton Floyd H.
Published: December 2023

The secreted phospholipase A2(sPLA2) isoform, sPLA2-IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA2-IIA. Through Genotype-Tissue Expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA2-IIA,PLA2G2A. SNP2TFBS (https://ccg.epfl.ch/snp2tfbs/) was utilized to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified SNPs. Subsequently, ChIP-seq peaks highlighted the TF combinations that specifically bind to the SNP, rs11573156. SP1 emerged as a significant TF/SNP pair in liver cells, with rs11573156/SP1 interaction being most prominent in liver, prostate, ovary, and adipose tissues. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was affected by tissue SP1 protein levels. By leveraging an ordinary differential equation, structured upon Michaelis-Menten enzyme kinetics assumptions, we modeled the PLA2G2A transcription’s dependence on SP1 protein levels, incorporating the SNP’s influence. Collectively, these data strongly suggest that the binding affinity differences of SP1 for the different rs11573156 alleles can influencePLA2G2Aexpression. This, in turn, can modulate sPLA2-IIA levels, impacting a wide range of human diseases.
Blood pressure variability, central autonomic network dysfunction and cerebral small vessel disease in APOE4 carriers
Authors: Lohman Trevor , Sible Isabel , Kapoor Arunima , Engstrom Allison C , Alitin John Paul , Gaubert Aimee , Rodgers Kathleen E , Bradford David , Mather Mara , Han S. Duke , Thayer Julian F. , Nation Daniel A
Published: December 2023

Background

Increased blood pressure variability (BPV) is a risk factor for cerebral small vessel disease (CSVD) and neurodegeneration, independent of age and average blood pressure, particularly in apolipoprotein E4 (APOE4) carriers. However, it remains uncertain whether BPV elevation is a cause or a consequence of vascular brain injury, or to what degree injury to the central autonomic network (CAN) may contribute to BPV-associated risk inAPOE4carriers.

Methods

Independently living older adults (n=70) with no history of stroke or dementia were recruited from the community and underwent 5 minutes of resting beat-to-beat blood pressure monitoring, genetic testing, and brain MRI. Resting BPV,APOEgenotype, CSVD burden on brain MRI, and resting state CAN connectivity by fMRI were analyzed. Causal mediation and moderation analysis evaluated BPV and CAN effects on CSVD inAPOE4carriers (n=37) and non-carriers (n=33).

Results

Higher BPV was associated with the presence and extent of CSVD inAPOE4carriers, but not non-carriers, independent of CAN connectivity (B= 18.92,P= .02), and CAN connectivity did not mediate the relationship between BPV and CSVD. InAPOE4carriers, CAN connectivity moderated the relationship between BPV and CSVD, whereby BPV effects on CSVD were greater in those with lower CAN connectivity (B= 36.43,P= .02).

Conclusions

OlderAPOE4carriers with higher beat-to-beat BPV exhibit more extensive CSVD, independent of average blood pressure, and the strength of CAN connectivity does not mediate these effects. Findings suggest increased BPV is more likely a cause, not a consequence, of CSVD. BPV is more strongly associated with CSVD inAPOE4carriers with lower rsCAN connectivity, suggesting CAN dysfunction and BPV elevation may have synergistic effects on CSVD. Further studies are warranted to understand the interplay between BPV and CAN function inAPOE4carriers.
Gut microbial and human genetic signatures of inflammatory bowel disease increase risk of comorbid mental disorders
Authors: Lee Junho , Oh Shin Ju , Ha Eunji , Shin Ga Young , Kim Hyo Jong , Kim Kwangwoo , Lee Chang Kyun
Published: December 2023

The high prevalence of comorbid mental disorders (CMDs), such as anxiety and depression, in patients with inflammatory bowel disease (IBD) is well documented. The reported bidirectional relationship between the two conditions suggests a crucial role of a gut-brain axis in CMD development in patients with IBD. This study aimed to investigate a complex interplay between gut microbiota and host genetic variants relevant to the development of CMDs in IBD. Genome-wide variant data, gut metagenomic data, and/or anxiety/depression estimates were obtained from 507 patients with IBD and 75 healthy controls. A series of integrative analyses were performed, profiling gut microbial diversity, microbial abundance, polygenic risk score, microbial quantitative trait locus (mbQTL), and microbial IBD-risk score. Patients with IBD had significantly lower gut microbial alpha diversity than controls, particularly those with CMD. Beta diversity revealed that a large fraction of IBD-associated taxa contributing to the top principal component were potentially associated with CMD risk. We identified 146 significantly differentially abundant taxa (DATs) between IBD patients and controls, and 48 DATs between CMD-free and CMD-affected IBD patients, with the majority showing consistent changes in abundance between IBD and CMD. Microbial IBD-risk scores, developed to estimate the degree of microbial IBD-specific burden in each individual, supported a significant enrichment of IBD-risk signatures in CMD-affected patients. Additionally, we found an IBD-risk mbQTL for an IBD/CMD-associated DAT, implicating an interplay between IBD-risk variants and gut dysbiosis in the development of both IBD and CMD. Collectively, IBD-associated gut dysbiosis predominantly confers risk of CMD in IBD patients partially through genetic variant-mediated regulation.
The curvilinear relationships between grand parity and incidence of hormone-dependent cancers; follow-up of postmenopausal women in the Norwegian 1960 Census
Authors: Lund Eiliv , Busund Lill-Tove Rasmussen , Holden Lars
Published: December 2023

Breast, ovarian and endometrial cancers are named hormone dependent cancers (HDC) because of the effects of endogenous hormones, including parity, on the incidence rates. Here, we will test the hypothesis that each additional child has the same relative preventive effect on the risk of each of the three cancer sites and with similar shapes of the incidence curves over the extended exposure range, 1 - 18 children in postmenopausal women.

The study is based on parity information from the Norwegian 1960 Census for women aged 45-89 years. A total of 385 816 married women answered the question of number of children in present marriage to a civil servant. Follow-up continued until the first of any of the HDC diagnosis, death, or end of follow-up 2005 through linkages based on the unique Norwegian birth number. Included were 16 905 breast cancers, 3 827 ovarian cancers and 3 834 endometrial cancers. Based on person-years (PY), the percentage change in incidence rates of the three cancer sites for each additional child was calculated using a logit regression model including models with higher order terms. A new statistical method for analyses of collinearity between parity and age at first birth has been developed. Age at marriage was used as a proxy for age at first birth.

Parity had strong linear effects on the incidence rates for all three cancer sites (p<2e-16). The percentage decrease for each of the cancer diagnosis for an additional child were for breast cancer 10.5% (95% CI; 9.6-11.4), ovarian cancer 13.2% (11.2-15.3) and endometrial cancer 10.9% (8.9-12.8) with similar curvilinear relationship. Models with higher order terms gave slightly better fit to the data with a stronger protective effect for increasing parity on ovarian cancers, while for breast cancer age became more important. Combining the incidence of all three cancers gave a percentage decrease for each additional child of 11.0% (10.1-11.8). The risk for HDC cancer was reduced with earlier age at marriage (first birth) for women with 1-2 children for breast cancer and ovarian cancer and 1 child for endometrial cancer, but the effect was smaller than one additional child. Age of the women at marriage was not significant for the sum of the three cancers.

The study demonstrated the strong, regular protective effect of each additional child or full-term pregnancy on the incidence rates of the hormone-dependent cancers throughout the exposure range and with similar curvilinear relations. Reduced fertility is a common, strong etiological factor for the three hormone-dependent cancers in postmenopausal women. These findings support a hypothesis that similar immunological changes during each pregnancy could be the biological explanation.
A novel human model to deconvolve cell-intrinsic phenotypes of genetically dysregulated pathways in lung squamous cell carcinoma
Authors: Ogden Julia , Sellers Robert , Sahoo Sudhakar , Oojageer Anthony , Chaturvedi Anshuman , Dive Caroline , Lopez-Garcia Carlos
Published: December 2023

Tractable, patient relevant models are needed to investigate cancer progression and heterogeneity. Here, we report an alternative and unique in vitro model of lung squamous cell carcinoma (LUSC) using primary human bronchial epithelial cells (hBECs) from three healthy donors. The co-operation of ubiquitous alterations (TP53andCDKN2Aloss) and components of commonly deregulated pathways including squamous differentiation (SOX2), PI3K signalling (PTEN) and the oxidative stress response (KEAP1) was investigated by generating hBECs harbouring cumulative alterations. Our analyses confirmed thatSOX2-overexpression initiates early preinvasive LUSC stages, and co-operation with the oxidative stress response and PI3K pathways to drive more aggressive phenotypes, with expansion of cells expressing LUSC biomarkers and invasive properties. This cooperation was consistent with the classical LUSC subtype. Importantly, we connected pathway dysregulation with gene expression changes associated with cell-intrinsic processes and immunomodulation. Our approach constitutes a powerful system to model LUSC and unravel genotype-phenotype causations of clinical relevance.
A Comparative Analysis of Imaging-Based Spatial Transcriptomics Platforms
Authors: Cook David P. , Jensen Kirk B. , Wise Kellie , Roach Michael J. , Dezem Felipe Segato , Ryan Natalie K. , Zamojski Michel , Vlachos Ioannis S. , Knott Simon R. V. , Butler Lisa M. , Wrana Jeffrey L. , Banovich Nicholas E. , Plummer Jasmine T. , Martelotto Luciano G.
Published: December 2023

Spatial transcriptomics is a rapidly evolving field, overwhelmed by a multitude of technologies. This study aims to offer a comparative analysis of datasets generated from leadingin situimaging platforms. We have generated spatial transcriptomics data from serial sections of prostate adenocarcinoma using the 10x Genomics Xenium and NanoString CosMx SMI platforms. Additionally, orthogonal single-nucleus RNA sequencing (snRNA-seq) was performed on the same FFPE tissue to establish a reference for the tumor’s transcriptional profiles. We assessed various technical aspects, such as reproducibility, sensitivity, dynamic range, cell segmentation, cell type annotation, and congruence with single-cell profiling. The practicality of assessing cellular organization and biomarker localization was evaluated. Although fewer genes are measured (CosMx: 960, Xenium: 377, with an overlap of 125), Xenium consistently demonstrates higher sensitivity, a broader dynamic range, and better alignment with single-cell reference profiles. Conversely, CosMx’s out-of-the-box segmentation outperformed Xenium’s, resulting in noticeable transcript misassignment in Xenium within certain tissue areas. However, the impact of this on the cells’ transcriptional profile was minimal. Together, this comprehensive comparison of two leading commercial platforms for spatial transcriptomics provides essential metrics for assessing their performance, offering invaluable insights for future research and technological advancements in this dynamic field.
Analysis of clinicalCandida parapsilosisisolates reveals copy number variation in key fluconazole resistance genes
Authors: Bergin Sean , Doorley Laura A. , Rybak Jeffrey M. , Wolfe Kenneth H. , Butler Geraldine , Cuomo Christina A. , Rogers P. David
Published: December 2023

We used whole-genome sequencing to analyse a collection of 35 fluconazole resistant and 7 susceptibleCandida parapsilosisisolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two probable outbreak groups were identified. We identified copy number variation of two genes,ERG11andCDR1B, in resistant isolates. Two strains have a CNV at theERG11locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show the annotated telomeric geneCDR1Bis actually an artefactualin silicofusion of two highly similar neighbouringCDRgenes due to an assembly error in theC. parapsilosisCDC317 reference genome. We report highly variable copy numbers of theCDR1Bregion across the collection. Several strains have increased expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across theCDRgene family in theC. parapsilosisspecies complex, showing that it is a highly dynamic family.
Peroxiredoxinylation buffers the redox state of the proteome upon cellular stress
Authors: Seisenbacher Gerhard , Raguz Nakic Zrinka , Borràs Eva , Sabidó Eduard , Sauer Uwe , de Nadal Eulalia , Posas Francesc
Published: December 2023

The redox state of proteins is essential for their function and guarantees cell fitness. Peroxiredoxins protect cells against oxidative stress, maintain redox homeostasis, act as chaperones and transmit hydrogen peroxide signals to redox regulators. Despite the profound structural and functional knowledge of peroxiredoxins action, information on how the different functions are concerted is still scare. Using global proteomic analyses, we show here that the yeast peroxiredoxin Tsa1 binds hundreds of proteins of essential biological processes, including protein turnover and carbohydrate metabolism. Several of these interactions are of covalent nature and failure of this peroxiredoxinylation leads to global changes in the metabolome and reduced stress resistance. Thioredoxins directly remove TSA1-formed mixed disulfide intermediates, thus expanding the role of the thioredoxin-peroxiredoxin redox cycle pair to buffer the redox state of proteins in an unprecedented way.
Massively parallel base editing screens to map variant effects on anti-tumor hallmarks of primary human T cells
Authors: Walsh Zachary H. , Shah Parin , Kothapalli Neeharika , Nikolenyi Gergo , Shah Shivem B. , Leuzzi Giuseppe , Mu Michael , Ho Patricia , Abuzaid Sinan , Brodtman Zack D. , Vasan Neil , AlQuraishi Mohammed , Milner Joshua D. , Ciccia Alberto , Melms Johannes C. , Izar Benjamin
Published: December 2023

Base editing enables generation of single nucleotide variants, but large-scale screening in primary human T cells is limited due to low editing efficiency, among other challenges1. Here, we developed a high-throughput approach for high-efficiency and massively parallel adenine and cytosine base-editor screening in primary human T cells. We performed multiple large-scale screens editing 102 genes with central functions in T cells and full-length tiling mutagenesis of selected genes, and read out variant effects on hallmarks of T cell anti-tumor immunity, including activation, proliferation, and cytokine production. We discovered a broad landscape of gain- and loss-of-function mutations, including inPIK3CDand its regulatory subunit encoded byPIK3R1, LCK,AKT1, CTLA-4andJAK1. We identified variants that affected several (e.g.,PIK3CDC416R) or only selected (e.g.LCKY505C) hallmarks of T cell activity, and functionally validated several hits by probing downstream signaling nodes and testing their impact on T cell polyfunctionality and proliferation. Using primary human T cells in which we engineered a T cell receptor (TCR) specific to a commonly presented tumor testis antigen as a model for cellular immunotherapy, we demonstrate that base edits identified in our screens can tune specific or broad T cell functions and ultimately improve tumor elimination while exerting minimal off-target activity. In summary, we present the first large-scale base editing screen in primary human T cells and provide a framework for scalable and targeted base editing at high efficiency. Coupled with multi-modal phenotypic mapping, we accurately nominate variants that produce a desirable T cell state and leverage these synthetic proteins to improve models of cellular cancer immunotherapies.
Recombine and succeed: a story of Cry toxins to expand the host range
Authors: Shikov Anton E. , Alagov Ruslan O. , Nizhnikov Anton A. , Belousova Maria E. , Antonets Kirill S.
Published: December 2023

Background

Cry toxins are the most widely used sources of bioinsecticides in agriculture; therefore, improving their functionality requires a deep understanding of natural evolution. It is thought that Cry toxins emerge via domain III swapping, yet the underlying mechanism remains unclear.

Results

We detected 50 recombination events using a dataset of 368 clusters representing a known diversity of Cry toxins using a computational analysis. Not only do domain swaps engage all the domains, but they also occur continuously with approximately 70% of toxins participating in domain exchanges. Once they happen, hybrid toxins face purifying selection pressure reflecting the advantageous nature of receiving novel domains. When these domain exchanges occur, their host specificity changes dramatically. Strains housing these loci are enriched withcrygenes and can kill a broader spectrum of hosts, thus implying that recombination allows them to occupy novel niches. The respective recombination-affectedcrygenes are flanked with insertions and harbor highly conservative blocks between the domains’ borders suggesting that the genomic context governs the intra-domain recombination.

Conclusions

Our study expands the established views of the role of recombination in the emergence of Cry toxins. Here, we demonstrate that the domain exchanges shape both Cry sequences, the composition of toxins in bacterial strains, and the sets of hosts affected. The collected data allowed us to propose a mechanism for how these toxins originate. Overall, the results suggest that domain exchanges have a profound impact on Cry toxins being a major evolutionary driver.