bluuebunny/crossref_metadata_2025 huggingface dataset:
Review targeted drug delivery systems for norcantharidin in cancer therapy
Authors: Zhai Bing-Tao , Sun Jing , Shi Ya-Jun , Zhang Xiao-Fei , Zou Jun-Bo , Cheng Jiang-Xue , Fan Yu , Guo Dong-Yan , Tian Huan
Published: December 2022

Norcantharidin (NCTD) is a demethylated derivative of cantharidin (CTD), the main anticancer active ingredient isolated from traditional Chinese medicine Mylabris. NCTD has been approved by the State Food and Drug Administration for the treatment of various solid tumors, especially liver cancer. Although NCTD greatly reduces the toxicity of CTD, there is still a certain degree of urinary toxicity and organ toxicity, and the poor solubility, short half-life, fast metabolism, as well as high venous irritation and weak tumor targeting ability limit its widespread application in the clinic. To reduce its toxicity and improve its efficacy, design of targeted drug delivery systems based on biomaterials and nanomaterials is one of the most feasible strategies. Therefore, this review focused on the studies of targeted drug delivery systems combined with NCTD in recent years, including passive and active targeted drug delivery systems, and physicochemical targeted drug delivery systems for improving drug bioavailability and enhancing its efficacy, as well as increasing drug targeting ability and reducing its adverse effects.

Graphical Abstract
Nanoparticles-mediated CRISPR-Cas9 gene therapy in inherited retinal diseases: applications, challenges, and emerging opportunities
Authors: Chien Yueh , Hsiao Yu-Jer , Chou Shih-Jie , Lin Ting-Yi , Yarmishyn Aliaksandr A. , Lai Wei-Yi , Lee Meng-Shiue , Lin Yi-Ying , Lin Tzu-Wei , Hwang De-Kuang , Lin Tai-Chi , Chiou Shih-Hwa , Chen Shih-Jen , Yang Yi-Ping
Published: December 2022

Inherited Retinal Diseases (IRDs) are considered one of the leading causes of blindness worldwide. However, the majority of them still lack a safe and effective treatment due to their complexity and genetic heterogeneity. Recently, gene therapy is gaining importance as an efficient strategy to address IRDs which were previously considered incurable. The development of the clustered regularly-interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) system has strongly empowered the field of gene therapy. However, successful gene modifications rely on the efficient delivery of CRISPR-Cas9 components into the complex three-dimensional (3D) architecture of the human retinal tissue. Intriguing findings in the field of nanoparticles (NPs) meet all the criteria required for CRISPR-Cas9 delivery and have made a great contribution toward its therapeutic applications. In addition, exploiting induced pluripotent stem cell (iPSC) technology and in vitro 3D retinal organoids paved the way for prospective clinical trials of the CRISPR-Cas9 system in treating IRDs. This review highlights important advances in NP-based gene therapy, the CRISPR-Cas9 system, and iPSC-derived retinal organoids with a focus on IRDs. Collectively, these studies establish a multidisciplinary approach by integrating nanomedicine and stem cell technologies and demonstrate the utility of retina organoids in developing effective therapies for IRDs.
Culture, church, and collective: a qualitative study about gambling harm prevention and reduction in Aotearoa/New Zealand—a Tongan male perspective
Authors: Fehoko Edmond S. , Bellringer Maria E. , Fairbairn-Dunlop Peggy
Published: December 2022

Background

In New Zealand, Pacific people continue to be more at risk of gambling harm than the general population, despite increasing public health efforts and treatment service provisions introduced to address this social and health issue. In looking at why this is so, our first concern was to ask why the delivery of the prevailing gambling-focussed programmes was not influencing Pacific gambling behaviours. In seeking to answer this question, it was important to explore ethnic-Pacific-specific factors of gambling harm prevention and reduction.

Methods

The research design was interpretivist/constructivist and phenomenological, applied through the lens of a Tongan worldview. Participants comprised Tongan male elders and youth. Recruitment of participants was through snowball sampling from churches and kava-drinking circles. A total of 28 elders and 18 youth participated through focus group talanoa and individual talanoa. This study employed descriptive thematic analysis.

Results

Participants were not aware of any policy document or problem-gambling preventative programmes. Four key themes were raised, which include raising the awareness of existing gambling harm treatment providers, the church influence in addressing gambling harm, community-based strategies, and cultural-based approaches.

Conclusions

This study proposes several recommendations such as more awareness of gambling harm providers in community, increasing cultural spaces and church engagements, and calls for further research in addressing the prevention and reduction of gambling harm amongst the Tongan community in New Zealand.
Participant perceptions on the acceptability and feasibility of a telemedicine-based HIV PrEP and buprenorphine/naloxone program embedded within syringe services programs: a qualitative descriptive evaluation
Authors: Corneli Amy , Perry Brian , Des Marais Andrea , Choi Yujung , Chen Hillary , Lilly Rebecca , Ayers Denae , Bennett Jesse , Kestner Lauren , Meade Christina S. , Sachdeva Nidhi , McKellar Mehri S.
Published: December 2022

Background

People who inject drugs (PWID) are at risk for HIV and opioid overdose. We piloted PARTNER UP, a telemedicine-based program to provide PWID with access to both oral pre-exposure prophylaxis (PrEP) for HIV prevention and medication for opioid use disorder (MOUD) through two syringe services programs (SSPs) in North Carolina. We conducted a qualitative evaluation to assess the acceptability and feasibility of PARTNER UP from the participant perspective.

Methods

PARTNER UP participants met with a provider for an initial in-person visit at the SSP, followed by weekly telemedicine visits in month 1 and then monthly telemedicine visits until program end at month 6. Using a qualitative descriptive study design, we conducted in-depth interviews with a subsample of PARTNER UP participants at 1 month and 4 months. Informed by the technology acceptance model, we assessed participant perceptions of the usefulness and ease of use of PARTNER UP, as well as their intent to continue to use the program’s components. We audio-recorded all interviews with participants’ permission and used applied thematic analysis to analyze the verbatim transcripts.

Results

We interviewed 11 of 17 people who participated in PARTNER UP—10 in the month 1 interview and 8 in the month 4 interview. Nearly all participants were motivated to join for consistent and easy access to buprenorphine/naloxone (i.e., MOUD); only a few joined to access PrEP. Most were comfortable accessing healthcare at the SSP because of their relationship with and trust toward SSP staff, and accessing services at the SSP was preferred compared with other healthcare centers. Some participants described that telemedicine allowed them to be honest and share more information because the visits were not in-person and they chose the location, although the initial in-person meeting was helpful to build provider trust and rapport. Most participants found the visit schedule to be feasible, although half described needing to reschedule at least once. Nearly all participants who were interviewed intended to continue with MOUD after the program ended, whereas none were interested in continuing with PrEP.

Conclusions

Participant narratives suggest that the PARTNER UP telemedicine program was acceptable and feasible. Future studies should continue to explore the benefits of embedding both PrEP and MOUD into SSPs with larger numbers of participants.

Trial registration Clinicaltrials.gov Identifier: NCT04521920.
“We want everything in a one-stop shop”: acceptability and feasibility of PrEP and buprenorphine implementation with mobile syringe services for Black people who inject drugs
Authors: Bartholomew Tyler S. , Andraka-Cristou Barbara , Totaram Rachel K. , Harris Shana , Doblecki-Lewis Susanne , Ostrer Lily , Serota David P. , Forrest David W. , Chueng Teresa A. , Suarez Edward , Tookes Hansel E.
Published: December 2022

Introduction

A recent surge in HIV outbreaks, driven by the opioid and stimulant use crises, has destabilized our progress toward targets set forth by Ending the HIV Epidemic: A Plan for America for the high-priority community of people who inject drugs (PWID), particularly Black PWID.

Methods

In order to ascertain the acceptability and feasibility of using a mobile syringe services program (SSP) for comprehensive HIV prevention via PrEP and medications for opioid use disorder (MOUD), our mixed methods approach included a quantitative assessment and semi-structured qualitative interviews with Black PWID (n = 30) in Miami-Dade County who were actively engaged in mobile syringe services.

Results

Participants felt that delivery of MOUD and PrEP at a mobile SSP would be both feasible and acceptable, helping to address transportation, cost, and stigma barriers common within traditional healthcare settings. Participants preferred staff who are compassionate and nonjudgmental and have lived experience.

Conclusions

A mobile harm reduction setting could be an effective venue for delivering comprehensive HIV prevention services to Black PWID, a community that experiences significant barriers to care via marginalization and racism in a fragmented healthcare system.
Prevalence and correlates of using opioids alone among individuals in a residential treatment program in Michigan: implications for overdose mortality prevention
Authors: Gicquelais Rachel E. , Genberg Becky L. , Maksut Jessica L. , Bohnert Amy S. B. , Fernandez Anne C.
Published: December 2022

Background

Avoiding use of opioids while alone reduces overdose fatality risk; however, drug use-related stigma may be a barrier to consistently using opioids in the presence of others.

Methods

We described the frequency of using opioids while alone among 241 people reporting daily heroin use or non-prescribed use of opioid analgesic medications (OAMs) in the month before attending a substance use disorder treatment program in the Midwestern USA. We investigated drug use-related stigma as a correlate of using opioids while alone frequently (very often vs. less frequently or never) and examined overdose risk behaviors associated with using opioids while alone frequently, adjusted for sociodemographic and clinical characteristics.

Results

The sample was a median age of 30 years, 34% female, 79% white, and nearly all (91%) had experienced an overdose. Approximately 63% had used OAMs and 70% used heroin while alone very often in the month before treatment. High levels of anticipated stigma were associated with using either opioid while alone very often (adjusted PR: 1.20, 95% CI: 1.04–1.38). Drinking alcohol and taking sedatives within two hours of OAMs very often (vs. less often or never) and using OAMs in a new setting very often (vs. less often or never) were associated with using OAMs while alone very often. Taking sedatives within two hours of using heroin and using heroin in a new setting very often (vs. less often or never) were associated with using heroin while alone very often.

Conclusion

Anticipated stigma, polysubstance use, and use in a new setting were associated with using opioids while alone. These findings highlight a need for enhanced overdose harm reduction options, such as overdose detection services that can initiate an overdose response if needed. Addressing stigmatizing behaviors in communities may reduce anticipated stigma and support engagement and trust in these services.
High VSX1 expression promotes the aggressiveness of clear cell renal cell carcinoma by transcriptionally regulating FKBP10
Authors: Ma Wenliang , Li Xin , Yang Lei , Pan Jun , Chen Yi , Lu Yanwen , Dong Xiang , Li Dongmei , Gan Weidong
Published: December 2022

Background

Clear cell renal cell carcinoma (ccRCC), the most common urological malignancy, has an unfavorable prognosis and an unknown mechanism of progression. Through survival analyses screening of The Cancer Genome Atlas (TCGA) dataset, we identified Visual system homeobox1 (VSX1) as a novel potential prognostic biomarker in ccRCC and subsequently investigated the oncogenic role of VSX1 in ccRCC.

Methods

The differential expression of VSX1 in human tumors and the clinical prognoses were analyzed in the TCGA dataset and Gene Expression Omnibus. Spearman’s correlation coefficient was determined for the correlation analysis of VSX1 expression and other genes of interest. The roles of VSX1 in cell proliferation, invasion, and migration of ccRCC cells were evaluated via the CCK-8 assay, colony formation assay, and Transwell assay, respectively. Further results were demonstrated by western blotting, immunohistochemistry, qRT-PCR, tumor sphere formation, flow cytometry, and the dual‑luciferase reporter assay.

Results

VSX1 mRNA upregulation was generally observed in multiple human malignancies from the TCGA database and was confirmed in ccRCC clinical specimens from our department. High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with ccRCC. In terms of mechanism, knockdown or overexpression of VSX1 affected ccRCC aggressiveness in vitro. The dual-luciferase reporter gene assay implied that VSX1 overexpression significantly increased the luciferase activity of TMEM44, FKBP10, and TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of these genes. The significantly enhanced growth in vitro that was induced by stable VSX1 overexpression was almost restored to normal by the knockdown of FKBP10.

Conclusions

This study demonstrated that VSX1 was a novel prognostic biomarker in ccRCC and that high VSX1 expression promoted cell proliferation, invasion, and migration in ccRCC via transcriptional activation of downstream target genes.
Heterogeneous matrix stiffness regulates the cancer stem-like cell phenotype in hepatocellular carcinoma
Authors: Wei Jiayun , Yao Jia , Yang Chendong , Mao Yongcui , Zhu Dan , Xie Ye , Liu Pinyan , Yan Mengchao , Ren Longfei , Lin Yan , Zheng Qiuxia , Li Xun
Published: December 2022

Background

Solid tumors are stiffer than their surrounding normal tissues; however, their interior stiffness is not uniform. Under certain conditions, cancer cells can acquire stem-like phenotypes. However, it remains unclear how the heterogeneous physical microenvironment affects stemness expression in cancer cells. Here, we aimed to evaluate matrix stiffness heterogeneity in hepatocellular carcinoma (HCC) tissues and to explore the regulation effect of the tumor microenvironment on stem-like phenotypic changes through mechanical transduction.

Methods

First, we used atomic force microscopy (AFM) to evaluate the elastic modulus of HCC tissues. We then used hydrogel with adjustable stiffness to investigate the effect of matrix stiffness on the stem-like phenotype expression of HCC cells. Moreover, cells cultured on hydrogel with different stiffness were subjected to morphology, real-time PCR, western blotting, and immunofluorescence analyses to explore the mechanotransduction pathway. Finally, animal models were used to validate in vitro results.

Results

AFM results confirmed the heterogenous matrix stiffness in HCC tissue. Cancer cells adhered to hydrogel with varying stiffness (1.10 ± 0.34 kPa, 4.47 ± 1.19 kPa, and 10.61 kPa) exhibited different cellular and cytoskeleton morphology. Higher matrix stiffness promoted the stem-like phenotype expression and reduced sorafenib-induced apoptosis. In contrast, lower stiffness induced the expression of proliferation-related protein Ki67. Moreover, mechanical signals were transmitted into cells through the integrin–yes-associated protein (YAP) pathway. Higher matrix stiffness did not affect YAP expression, however, reduced the proportion of phosphorylated YAP, promoted YAP nuclear translocation, and regulated gene transcription. Finally, application of ATN-161 (integrin inhibitor) and verteporfin (YAP inhibitor) effectively blocked the stem-like phenotype expression regulated by matrix stiffness.

Conclusions

Our experiments provide new insights into the interaction between matrix stiffness, cancer cell stemness, and heterogeneity, while also providing a novel HCC therapeutic strategy.
Evidence of innate immune dysfunction in first-episode psychosis patients with accompanying mood disorder
Authors: Hughes Heather K. , Yang Houa , Lesh Tyler A. , Carter Cameron S. , Ashwood Paul
Published: December 2022

Background

Inflammation and increases in inflammatory cytokines are common findings in psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). Meta-analyses of studies that measured circulating cytokines have provided evidence of innate inflammation across all three disorders, with some overlap of inflammatory cytokines such as IL-6 and TNF-α. However, differences across disorders were also identified, including increased IL-4 in BD that suggest different immune mechanisms may be involved depending on the type of disorder present.

Methods

We sought to identify if the presence or absence of an affective disorder in first-episode psychotic (FEP) patients was associated with variations in cytokine production after stimulation of peripheral blood mononuclear cells (PBMC). 98 participants were recruited and grouped into healthy controls (n = 45) and first-episode psychosis patients (n = 53). Psychosis patients were further grouped by presence (AFF; n = 22) or lack (NON; n = 31) of an affective disorder. We cultured isolated PBMC from all participants for 48 h at 37 °C under four separate conditions; (1) culture media alone for baseline, or the following three stimulatory conditions: (2) 25 ng/mL lipopolysaccharide (LPS), (3) 10 ng/mL phytohemagglutinin (PHA), and (4) 125 ng/ml α-CD3 plus 250 ng/ml α-CD28. Supernatants collected at 48 h were analyzed using multiplex Luminex assay to identify differences in cytokine and chemokine production. Results from these assays were then correlated to patient clinical assessments for positive and negative symptoms common to psychotic disorders.

Results

We found that PBMC from affective FEP patients produced higher concentrations of cytokines associated with both innate and adaptive immunity after stimulation than non-affective FEP patients and healthy controls. More specifically, the AFF PBMC produced increased tumor necrosis fctor (TNF)-α, interleukin (IL)-1β, IL-6, and others associated with innate inflammation. PBMC from AFF also produced increased IL-4, IL-17, interferon (IFN)γ, and other cytokines associated with adaptive immune activation, depending on stimulation. Additionally, inflammatory cytokines that differed at rest and after LPS stimulation correlated with Scale for the Assessment of Negative Symptoms (SANS) scores.

Conclusions

Our findings suggest that immune dysfunction in affective psychosis may differ from that of primary psychotic disorders, and inflammation may be associated with increased negative symptoms. These findings could be helpful in determining clinical diagnosis after first psychotic episode.
TREM2 activation alleviates neural damage via Akt/CREB/BDNF signalling after traumatic brain injury in mice
Authors: Yan Jin , Zhang Yuan , Wang Lin , Li Zhao , Tang Shuang , Wang Yingwen , Gu Nina , Sun Xiaochuan , Li Lin
Published: December 2022

Background

Neuroinflammation is one of the most important processes in secondary injury after traumatic brain injury (TBI). Triggering receptor expressed on myeloid cells 2 (TREM2) has been proven to exert neuroprotective effects in neurodegenerative diseases and stroke by modulating neuroinflammation, and promoting phagocytosis and cell survival. However, the role of TREM2 in TBI has not yet been elucidated. In this study, we are the first to use COG1410, an agonist of TREM2, to assess the effects of TREM2 activation in a murine TBI model.

Methods

Adult male wild-type (WT) C57BL/6 mice and adult male TREM2 KO mice were subjected to different treatments. TBI was established by the controlled cortical impact (CCI) method. COG1410 was delivered 1 h after CCI via tail vein injection. Western blot analysis, immunofluorescence, laser speckle contrast imaging (LSCI), neurological behaviour tests, brain electrophysiological monitoring, Evans blue assays, magnetic resonance imaging (MRI), and brain water content measurement were performed in this study.

Results

The expression of endogenous TREM2 peaked at 3 d after CCI, and it was mainly expressed on microglia and neurons. We found that COG1410 improved neurological functions within 3 d, as well as neurological functions and brain electrophysiological activity at 2 weeks after CCI. COG1410 exerted neuroprotective effects by inhibiting neutrophil infiltration and microglial activation, and suppressing neuroinflammation after CCI. In addition, COG1410 treatment alleviated blood brain barrier (BBB) disruption and brain oedema; furthermore, COG1410 promoted cerebral blood flow (CBF) recovery at traumatic injury sites after CCI. In addition, COG1410 suppressed neural apoptosis at 3 d after CCI. TREM2 activation upregulated p-Akt, p-CREB, BDNF, and Bcl-2 and suppressed TNF-α, IL-1β, Bax, and cleaved caspase-3 at 3 d after CCI. Moreover, TREM2 knockout abolished the effects of COG1410 on vascular phenotypes and microglial states. Finally, the neuroprotective effects of COG1410 were suppressed by TREM2 depletion.

Conclusions

Altogether, we are the first to demonstrate that TREM2 activation by COG1410 alleviated neural damage through activation of Akt/CREB/BDNF signalling axis in microglia after CCI. Finally, COG1410 treatment improved neurological behaviour and brain electrophysiological activity after CCI.

Graphical Abstract
Practices and attitudes towards tuberculosis and latent tuberculosis infection screening in people living with HIV/AIDS among HIV physicians in Japan
Authors: Kawatsu Lisa , Kaneko Noriyo , Imahashi Mayumi , Kamada Keisuke , Uchimura Kazuhiro
Published: December 2022

Background

Tuberculosis (TB) continues to be the leading cause of death for people living with HIV/AIDS (PLHIV), and HIV is the strongest known risk factor for progression to active TB disease for persons with latent TB infection (LTBI). Screening for active TB and LTBI, and TB preventive therapy (TPT) is recommended, however, clinical practices regarding LTBI screening for HIV positive population have not been uniform, resulting in low rates of LTBI screening and TPT uptake, in both low and high TB-burden countries. We sought to explore the practices and attitudes towards TB and LTBI screening in PLHIV among HIV physicians in Japan.

Methods

We conducted a cross-sectional survey whereby an on-line questionnaire was administered to physicians who are currently, or have the experience of, providing care and treatment for PLHIV in Japan.

Results

The questionnaire was sent to a total of 83 physicians, of which 59 responded (response rate; 71.1%). 52.5% (31/59) conducted routine screening and 44.0% (26/59) conducted selectively screening for active TB among HIV/AIDS patients. As for LTBI, 54.2% (32/59) conducted routine screening and 35.6% (21/59) conducted selective screening for LTBI among PLHIV. “T-SPOT only” was the most frequently used method of screening (n = 33), followed by “QFT only” (n = 11). Criteria for LTBI screening included TB burden in the country of birth of the patient, previous contact with a TB patient, and CD4+ cell count. 83.1% (49/59) either “always” or “selectively” offered TPT to PLHIV diagnosed with LTBI, and among the 49 respondents who did provide TPT, 77.6% (38/49) chose 9-months isoniazid as their first choice. None chose regimen including rifampicin.

Conclusions

Our study revealed that practices regarding TB and LTBI screening and treatment for PLHIV among HIV physicians were mixed and not necessarily in accordance with the various published guidelines. Building and disseminating scientific evidence that takes into consideration the local epidemiology of TB and HIV in Japan is urgently needed to assist physicians make decisions.
Is plasma amyloid-β 1–42/1–40 a better biomarker for Alzheimer’s disease than AβX–42/X–40?
Authors: Klafki Hans-Wolfgang , Morgado Barbara , Wirths Oliver , Jahn Olaf , Bauer Chris , Esselmann Hermann , Schuchhardt Johannes , Wiltfang Jens
Published: December 2022

Background

A reduced amyloid-β (Aβ)42/40 peptide ratio in blood plasma represents a peripheral biomarker of the cerebral amyloid pathology observed in Alzheimer’s disease brains. The magnitude of the measurable effect in plasma is smaller than in cerebrospinal fluid, presumably due to dilution by Aβ peptides originating from peripheral sources. We hypothesized that the observable effect in plasma can be accentuated to some extent by specifically measuring Aβ1–42 and Aβ1–40 instead of AβX–42 and AβX–40.

Methods

We assessed the plasma AβX–42/X–40 and Aβ1–42/1–40 ratios in an idealized clinical sample by semi-automated Aβ immunoprecipitation followed by closely related sandwich immunoassays. The amyloid-positive and amyloid-negative groups (dichotomized according to Aβ42/40 in cerebrospinal fluid) were compared regarding the median difference, mean difference, standardized effect size (Cohen’s d) and receiver operating characteristic curves. For statistical evaluation, we applied bootstrapping.

Results

The median Aβ1–42/1–40 ratio was 20.86% lower in amyloid-positive subjects than in the amyloid-negative group, while the median AβX–42/X–40 ratio was only 15.56% lower. The relative mean difference between amyloid-positive and amyloid-negative subjects was −18.34% for plasma Aβ1–42/1–40 compared to −15.50% for AβX–42/X–40. Cohen’s d was 1.73 for Aβ1–42/1–40 and 1.48 for plasma AβX–42/X–40. Unadjusted p-values < 0.05 were obtained after .﻿﻿632 bootstrapping for all three parameters. Receiver operating characteristic analysis indicated very similar areas under the curves for plasma Aβ1–42/1–40 and AβX–42/X–40.

Conclusions

Our findings support the hypothesis that the relatively small difference in the plasma Aβ42/40 ratio between subjects with and without evidence of brain amyloidosis can be accentuated by specifically measuring Aβ1–42/1–40 instead of AβX–42/X–40. A simplified theoretical model explaining this observation is presented.
Exogenous laminin exhibits a unique vascular pattern in the brain via binding to dystroglycan and integrins
Authors: Ruan Jingsong , McKee Karen K. , Yurchenco Peter D. , Yao Yao
Published: December 2022

Background

Unlike other proteins that exhibit a diffusion pattern after intracerebral injection, laminin displays a vascular pattern. It remains unclear if this unique vascular pattern is caused by laminin-receptor interaction or laminin self-assembly.

Methods

We compared the distribution of various wild-type laminin isoforms in the brain after intracerebral injection. To determine what causes the unique vascular pattern of laminin in the brain, laminin mutants with impaired receptor-binding and/or self-assembly activities and function-blocking antibodies to laminin receptors were used. In addition, the dynamics of laminin distribution and elimination were examined at multiple time points after intracerebral injection.

Results

We found that β2-containing laminins had higher affinity for the vessels compared to β1-containing laminins. In addition, laminin mutants lacking receptor-binding domains but not that lacking self-assembly capability showed substantially reduced vascular pattern. Consistent with this finding, dystroglycan (DAG1) function-blocking antibody significantly reduced the vascular pattern of wild-type laminin-111. Although failed to affect the vascular pattern when used alone, integrin-β1 function-blocking antibody further decreased the vascular pattern when combined with DAG1 antibody. EDTA, which impaired laminini-DAG1 interaction by chelating Ca2+, also attenuated the vascular pattern. Immunohistochemistry revealed that laminins were predominantly located in the perivascular space in capillaries and venules/veins but not arterioles/arteries. The time-course study showed that laminin mutants with impaired receptor-engaging activity were more efficiently eliminated from the brain compared to their wild-type counterparts. Concordantly, significantly higher levels of mutant laminins were detected in the cerebral-spinal fluid (CSF).

Conclusions

These findings suggest that intracerebrally injected laminins are enriched in the perivascular space in a receptor (DAG1/integrin)-dependent rather than self-assembly-dependent manner and eliminated from the brain mainly via the perivascular clearance system.
Mental health assessment of healthcare workers in the emergency department of a low middle-income country during COVID-19 pandemic
Authors: Waheed Shahan , Kumar Nirdosh , Qureshi Bushra Qaiser , Rahim Ahmed
Published: December 2022

Introduction

Emergency department (ED) healthcare workers in Pakistan during the COVID-19 pandemic are facing an acute rise in mental illnesses. In this study, the authors aim to assess the frequency of anxiety and depression among healthcare workers in the ED.

Methods

A cross-sectional online google form-based survey was conducted in the ED of Aga Khan University Hospital, Karachi, Pakistan between July and August 2020. The Hospital Anxiety and Depression (HAD) scale was used for mental illness assessment among ED healthcare workers. Descriptive analysis of grading as per the Likert scale is done through frequencies, means, and standard deviations. Categorical variables were expressed as frequency (%). Mann–WhitneyUtest was used to compare scores of various groups and sub-groups and the Chi-square test was used to assess the association of depression and anxiety categories among the groups.

Results

In the ED, 127 healthcare workers (physicians and nurses) were included in this survey. The median depression score was 8 (IQR 6–10) with 21% (27) falling under depression and 39% (50) under borderline depression. The median anxiety score was 9 (IQR 7–12) with 33% (42) having abnormal, and 38% (48) having borderline anxiety. Healthcare workers working for > 45 h per week have odds of 3.62 [1.374–9.549] of developing depression compared to anxiety with ap-value of 0.009. Similarly, nurses and medical officers develop depression with odds of 2.18 [1.016–4.686]p-value 0.045 and 5.18 [0.197–1.02]p-value 0.002, respectively.

Conclusion

ED healthcare workers during the COVID-19 pandemic suffered high levels of anxiety and depression, which is a matter of concern. Comprehensive support and training of ED healthcare workers are needed to promote physical and mental well-being and to develop guidelines that should be used during situations that can affect the mental health of healthcare workers.
Metastatic colorectal cancer as the primary phenotype in a hereditary breast and ovarian cancer patient with Germline BRCA1 mutation: a case report
Authors: Liu Ying , Zhu Jing , Wei Xiao , Yang Duoxia , Li Si , Qian Xiaoping , Li Li
Published: December 2022

Hereditary breast and ovarian cancer (HBOC) syndrome has increased predisposition to breast and/or ovarian cancer, and 24% of families with HBOC were associated with the germline pathogenic variants in BRCA1/2. Timely diagnosis and identification of mutation carriers is of utmost importance to improve survival benefit and quality of life. Cancers that have been included into screening of BRCA1/2 associated HBOC included prostate and pancreatic cancers etc. In this case, we reported a patient who firstly presented symptoms of CRC and was finally diagnosed as BRCA1 associated HBOC with advanced peritoneal carcinoma. With strategies of cetuximab based treatment and olaparib, and debulking surgeries, she has achieved an overall survival (OS) > 35 months. The aim was to indicate that HBOC might also first present as CRC, and comprehensive next-generation sequencing analysis might be a key complement for screening and diagnose of HBOC.
Shaking up the silence: consequences of HMGN1 antagonizing PRC2 in the Down syndrome brain
Authors: Farley Sean J. , Grishok Alla , Zeldich Ella
Published: December 2022

Intellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), expressed from HSA21, is a chromatin remodeling protein that facilitates chromatin decompaction and is associated with acetylated lysine 27 on histone H3 (H3K27ac), a mark correlated with active transcription. Recent studies causatively linked overexpression of HMGN1 in trisomy and the development of DS-associated B cell acute lymphoblastic leukemia (B-ALL). HMGN1 has been shown to antagonize the activity of the Polycomb Repressive Complex 2 (PRC2) and prevent the deposition of histone H3 lysine 27 trimethylation mark (H3K27me3), which is associated with transcriptional repression and gene silencing. However, the possible ramifications of the increased levels of HMGN1 through the derepression of PRC2 target genes on brain cell pathology have not gained attention. In this review, we discuss the functional significance of HMGN1 in brain development and summarize accumulating reports about the essential role of PRC2 in the development of the neural system. Mechanistic understanding of how overexpression of HMGN1 may contribute to aberrant brain cell phenotypes in DS, such as altered proliferation of neural progenitors, abnormal cortical architecture, diminished myelination, neurodegeneration, and Alzheimer’s disease-related pathology in trisomy 21, will facilitate the development of DS therapeutic approaches targeting chromatin.
Helicobacter pylori infection: is there circulating vacuolating cytotoxin A or cytotoxin-associated gene A protein?
Authors: Imoto Ichiro , Oka Satoko , Katsurahara Masaki , Nakamura Misaki , Yasuma Taro , Akada Junko , D’Alessandro-Gabazza Corina N. , Toda Masaaki , Horiki Noriyuki , Gabazza Esteban C. , Yamaoka Yoshio
Published: December 2022

Background

Helicobacter pyloriinfection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis ofH. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients withH. pyloriinfection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released byH. pyloriin the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum.

Results

Sixty-two subjects were enrolled. They were allocated intothe H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients withoutH. pyloriinfection) were considered positive for antigen circulating level. Five out of 25H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti-H. pyloriantibody and interleukin-12p70 among allH. pylori-positive and H. pylori-negative patients.

Conclusions

This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients withH. pyloriinfection.
CAULIFINDER: a pipeline for the automated detection and annotation of caulimovirid endogenous viral elements in plant genomes
Authors: Vassilieff Héléna , Haddad Sana , Jamilloux Véronique , Choisne Nathalie , Sharma Vikas , Giraud Delphine , Wan Mariène , Serfraz Saad , Geering Andrew D. W. , Teycheney Pierre-Yves , Maumus Florian
Published: December 2022

Plant, animal and protist genomes often contain endogenous viral elements (EVEs), which correspond to partial and sometimes entire viral genomes that have been captured in the genome of their host organism through a variety of integration mechanisms. While the number of sequenced eukaryotic genomes is rapidly increasing, the annotation and characterization of EVEs remains largely overlooked. EVEs that derive from members of the family Caulimoviridae are widespread across tracheophyte plants, and sometimes they occur in very high copy numbers. However, existing programs for annotating repetitive DNA elements in plant genomes are poor at identifying and then classifying these EVEs. Other than accurately annotating plant genomes, there is intrinsic value in a tool that could identify caulimovirid EVEs as they testify to recent or ancient host-virus interactions and provide valuable insights into virus evolution. In response to this research need, we have developed CAULIFINDER, an automated and sensitive annotation software package. CAULIFINDER consists of two complementary workflows, one to reconstruct, annotate and group caulimovirid EVEs in a given plant genome and the second to classify these genetic elements into officially recognized or tentative genera in the Caulimoviridae. We have benchmarked the CAULIFINDER package using the Vitis vinifera reference genome, which contains a rich assortment of caulimovirid EVEs that have previously been characterized using manual methods. The CAULIFINDER package is distributed in the form of a Docker image.
Variations of generalized weak contractions in partially ordered b-metric space
Authors: Rao N. Seshagiri , Kalyani K.
Published: December 2022

Objectives

This paper explored the fixed point results for the mappings satisfying generalized weak contractive conditions in a complete partially ordered b-metric space. These contractions are some variations of the work done by the authors (Mituku et al. in BMC Res Notes 13:537. https://doi.org/10.1186/s13104-020-05354-1, 2020; Seshagiri et al. in BMC Res Notes 13:451. https://doi.org/10.1186/s13104-020-05273-1, 2020, BMC Res Notes 14:390. https://doi.org/10.1186/s13104-021-05801-7, 2021, BMC Res Notes 14:263. https://doi.org/10.1186/s13104-021-05649-x, 2021) in the same context. To validate the results a few examples are provided.

Result

The aim of this work is to prove some fixed point results of the self mappings in ordered b-metric space satisfying variant generalized weak contraction conditions. These results generalize some known results in the provided literature.
Cervical pre-cancerous lesion detection: development of smartphone-based VIA application using artificial intelligence
Authors: Harsono Ali Budi , Susiarno Hadi , Suardi Dodi , Owen Louis , Fauzi Hilman , Kireina Jessica , Wahid Rizki Amalia , Carolina Johanna Sharon , Mantilidewi Kemala Isnainiasih , Hidayat Yudi Mulyana
Published: December 2022

Objective

Visual inspection of cervix after acetic acid application (VIA) has been considered an alternative to Pap smear in resource-limited settings, like Indonesia. However, VIA results mainly depend on examiner’s experience and with the lack of comprehensive training of healthcare workers, VIA accuracy keeps declining. We aimed to develop an artificial intelligence (AI)-based Android application that can automatically determine VIA results in real time and may be further developed as a health care support system in cervical cancer screening.

Result

A total of 199 women who underwent VIA test was studied. Images of cervix before and after VIA test were taken with smartphone, then evaluated and labelled by experienced oncologist as VIA positive or negative. Our AI model training pipeline consists of 3 steps: image pre-processing, feature extraction, and classifier development. Out of the 199 data, 134 were used as train-validation data and the remaining 65 data were used as test data. The trained AI model generated a sensitivity of 80%, specificity of 96.4%, accuracy of 93.8%, precision of 80%, and ROC/AUC of 0.85 (95% CI 0.66–1.0). The developed AI-based Android application may potentially aid cervical cancer screening, especially in low resource settings.
A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence
Authors: Heumann Thatcher R. , Baretti Marina , Sugar Elizabeth A. , Durham Jennifer N. , Linden Sheila , Lopez-Vidal Tamara Y. , Leatherman James , Cope Leslie , Sharma Anup , Weekes Colin D. , O’Dwyer Peter J. , Reiss Kim A. , Monga Dulabh K. , Ahuja Nita , Azad Nilofer S.
Published: December 2022

Background

Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy.

Methods

This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19–9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1–21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)—time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting.

Results

Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36–81), 53% male, 73% node positive, 49% elevated CA 19–9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9–36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46–1.87,p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46–2.05,p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms.

Conclusions

Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.
The association of accelerated epigenetic age with all-cause mortality in cardiac catheterization patients as mediated by vascular and cardiometabolic outcomes
Authors: Jiang Rong , Hauser Elizabeth R. , Kwee Lydia Coulter , Shah Svati H. , Regan Jessica A. , Huebner Janet L. , Kraus Virginia B. , Kraus William E. , Ward-Caviness Cavin K.
Published: December 2022

Background

Epigenetic age is a DNA methylation-based biomarker of aging that is accurate across the lifespan and a range of cell types. The difference between epigenetic age and chronological age, termed age acceleration (AA), is a strong predictor of lifespan and healthspan. The predictive capabilities of AA for all-cause mortality have been evaluated in the general population; however, its utility is less well evaluated in those with chronic conditions. Additionally, the pathophysiologic pathways whereby AA predicts mortality are unclear. We hypothesized that AA predicts mortality in individuals with underlying cardiovascular disease; and the association between AA and mortality is mediated, in part, by vascular and cardiometabolic measures.

Methods

We evaluated 562 participants in an urban, three-county area of central North Carolina from the CATHGEN cohort, all of whom received a cardiac catheterization procedure. We analyzed three AA biomarkers, Horvath epigenetic age acceleration (HAA), phenotypic age acceleration (PhenoAA), and Grim age acceleration (GrimAA), by Cox regression models, to assess whether AAs were associated with all-cause mortality. We also evaluated if these associations were mediated by vascular and cardiometabolic outcomes, including left ventricular ejection fraction (LVEF), blood cholesterol concentrations, angiopoietin-2 (ANG2) protein concentration, peripheral artery disease, coronary artery disease, diabetes, and hypertension. The total effect, direct effect, indirect effect, and percentage mediated were estimated using pathway mediation tests with a regression adjustment approach.

Results

PhenoAA (HR = 1.05, P < 0.0001), GrimAA (HR = 1.10, P < 0.0001) and HAA (HR = 1.03, P = 0.01) were all associated with all-cause mortality. The association of mortality and PhenoAA was partially mediated by ANG2, a marker of vascular function (19.8%, P = 0.016), and by diabetes (8.2%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and showed weaker evidence for mediation by LVEF (5.3%, P = 0.065).

Conclusions

Epigenetic age acceleration remains strongly predictive of mortality even in individuals already burdened with cardiovascular disease. Mortality associations were mediated by ANG2, which regulates endothelial permeability and angiogenic functions, suggesting that specific vascular pathophysiology may link accelerated epigenetic aging with increased mortality risks.
LncRNAs ENST00000499459 and TCONS_00004989 enhance asthma progression in children with house dust mite-induced allergic asthma
Authors: Xude Zhang , Shaojie Feng , Beibei Guo , Jingjing Liu , Donghua Xu , Fengxia Liu
Published: December 2022

Background

Long non-coding RNAs (lncRNAs) have been extensively reported to play critical roles in the pathogenesis of various disease, especially in cancer. However, little is known about the role of lncRNAs in the pathogenesis of pediatric allergic asthma.

Methods

High-throughput sequencing analysis was performed to identify differentially expressed mRNAs and lncRNAs in peripheral blood mononuclear cells (PBMCs) from 3 children with allergic asthma and 3 matched healthy controls. Bioinformatics analysis was used to select candidate lncRNAs and mRNAs that may be involved in the pathogenesis of asthma. Candidate lncRNAs were validated in a larger size of asthma patients and healthy controls. Finally, lncRNAs and molecular pathways associated with the pathogenesis of allergic asthma were identified by competing endogenous RNA (ceRNA) analysis.

Results

Five differentially expressed lncRNAs were identified after high-throughput sequencing and verified by real-time PCR. LncRNAs ENST0000631797, TCONS_00004989 and ENST00000499459 were verified to be differentially expressed in allergic asthma. Besides, ENST00000499459/DIXDC1 axis was identified to play a crucial role in allergic asthma after comprehensive ceRNA network analysis.

Conclusion

ENST00000499459 and TCONS_00004989 are potential biomarkers for house dust mite-induced allergic asthma.