bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frailty and its association with health-related quality of life among older cancer patients: an evidence-based study from China
Authors: Su Mingzhu , Yao Nengliang , Shang Meimei , Shen Yuzhen , Qin Tingting , Wang Jialin , Sun Xiaojie 
Published: August 2022

Abstract
Background
There is limited information about the population characteristics and adverse health outcomes of older cancer patients in China. This study aimed to describe the prevalence of frailty and examine the association between frailty and health-related quality of life (HRQoL) among older cancer patients.

Methods
This was a cross-sectional study involving older patients diagnosed with cancer in two tertiary hospitals in Shandong Province, China. Frailty was assessed using Geriatric 8 (G-8). HRQoL was measured using the five-level EuroQol-5-dimension (EQ-5D-5L) questionnaire. The Tobit regression model and logistic regression model was used to identify the relationship between frailty and HRQoL.

Results
Of the 229 older patients, 175 (76.4%) were frail. Frail patients had lower EQ-5D-5L utility scores than those who were non-frail (0.830 vs. 0.889; P = 0.004). After adjustments for sociodemographic and cancer-related variables, frailty was statistically associated with worse health-related quality of life (OR = 6.024; P = 0.001).

Conclusion
Frailty was associated with deteriorated HRQoL in older patients with cancer. Early frailty screening and preventive interventions are essential for improving quality of life through decision-making or pretreatment optimization in geriatric oncology.
A novel inflammatory response-related signature predicts the prognosis of cutaneous melanoma and the effect of antitumor drugs
Authors: Xing Jiahua , Li Yan , Chen Youbai , Han Yan 
Published: August 2022

AbstractCutaneous melanoma (CM) is a skin cancer that is highly metastatic and aggressive, with a dismal prognosis. This is the first study to use inflammatory response-related genes to build a model and evaluate their predictive significance in CM. This study used public databases to download CM patients’ mRNA expression profiles and clinical data to create multigene prognostic markers in the UCSC cohort. We compared overall survival (OS) between high- and low-risk groups using the Kaplan-Meier curve and determined independent predictors using Cox analysis. We also used enrichment analysis to assess immune cell infiltration fraction and immune pathway-related activity using KEGG enrichment analysis. Furthermore, we detected prognostic genes’ mRNA and protein expression in CM and normal skin tissues using qRT-PCR and immunohistochemistry. Finally, we developed a 5-gene predictive model that showed that patients in the high-risk group had a considerably shorter OS than those in the low-risk group. The analysis of the receiver operating characteristic (ROC) curve proved the model’s predictive ability. We also conducted a drug sensitivity analysis and discovered that the expression levels of prognostic genes were substantially linked with cancer cell sensitivity to antitumor medicines. The findings show that the model we developed, which consists of five inflammatory response-related genes, can be used to forecast the prognosis and immunological state of CM, giving personalized and precision medicine a new goal and direction.
Effect of Notch1 signaling on cellular proliferation and apoptosis in human laryngeal carcinoma
Authors: Li Dawei , Xu Dan , Zhang Yifei , Chen Penghui , Xie Jin 
Published: August 2022

Abstract
Background
The occurrence and development of malignancies include excessive proliferation and apoptosis resistance in tumor cells. This study aimed to identify the effects of Notch1 signaling on proliferation and apoptosis of laryngeal cancer cells in a hypoxic microenvironment.

Methods
Notch1 and Ki-67 expression in laryngeal squamous cell carcinoma (LSCC) tissues was detected by immunohistochemistry. The apoptotic index (AI) of LSCC was evaluated by the TUNEL method. Small interfering RNA (siRNA) was used to inhibit Notch1 expression in laryngeal cancer cells. Real-time PCR was used to measure Notch1, Hes1, and Hey1 mRNA expression, and Western blotting was used to measure Notch1 and Notch1 intracellular domain (N1ICD) protein expression. Annexin V-FITC/propidium iodide staining and Cell Counting Kit-8 assays were used to measure cell apoptosis and proliferation, respectively.

Results
Notch1 expression was significantly related to the proliferation index (PI) and AI in LSCC tissues. Hypoxia could induce proliferation and inhibit apoptosis in cancer cells. Notch1 expression and Notch1 signaling activity could be upregulated by hypoxia. Suppressing Notch1 signaling activity in hypoxic cells could decrease proliferation and increase apoptosis.

Conclusions
Our study has demonstrated that hypoxia may promote proliferation and inhibit apoptosis of laryngeal cancer cells. Notch1 signaling may play a pivotal role in regulating the proliferation and apoptosis resistance of laryngeal cancer cells under hypoxic conditions.
hUCMSCs reduce theca interstitial cells apoptosis and restore ovarian function in premature ovarian insufficiency rats through regulating NR4A1-mediated mitochondrial mechanisms
Authors: Luo Qianqian , Tang Yu , Jiang Zhonglin , Bao Hongchu , Fu Qiang , Zhang Hongqin 
Published: August 2022

Abstract
Background
Human umbilical cord mesenchymal stem cells (hUCMSCs, retrospectively registered) have a lot of promise for treating theca interstitial cells(TICs) dysfunction in premature ovarian insufficiency (POI). The mechanisms, however, are still unknown.

Methods
To examine the therapeutic and find the cause, we used both in vivo cisplatin-induced POI rat model and in vitro TICs model. HUCMSCs were injected into the tail veins of POI rats in an in vivo investigation. Then, using ELISA, HE staining, TUNEL apoptosis test kit, immunohistochemistry and western blot, researchers examined hormonal levels, ovarian morphology, TICs apoptosis, NR4A1 and Cyp17a1 in response to cisplatin treatment and hUCMSCs. TICs were obtained from the ovaries of rats and treated with the cisplatin, hUCMSCs supernatant, and the antagonist of NR4A1——DIM-C-pPhOH. ELISA, immunofluorescence, flow cytometry, JC-1 labeling and western blot analysis were used to detect T levels, Cyp17a1, NR4A1, and the anti-apoptotic protein Bcl-2, as well as pro-apoptotic proteins Bax, caspase-9, caspase-3, and cytochrome C(cytc).

Results
We discovered that hUCMSCs restored the ovarian function, particularly TICs function based on measures of Cyp17a1 and T expression. NR4A1 was found in ovarian TICs of each group and NR4A1 expression was lower in the POI rats but higher following hUCMSCs therapy. The apoptosis of TICs generated by cisplatin was reduced after treatment with hUCMSCs. In vitro, NR4A1 was expressed in the nucleus of TICs, and NR4A1 as well as phospho-NR4A1 were decreased, following the apoptosis of TICs was emerged after cisplatin treatment. Interestingly, the localization of NR4A1 was translocated from the nucleus to the cytoplasm due to cisplatin. HUCMSCs were able to boost NR4A1 and phospho-NR4A1 expression while TICs’ apoptosis and JC-1 polymorimonomor fluorescence ratios reduced. Furthermore, Bcl-2 expression dropped following cisplatin treatment, whereas Bax, cytc, caspase-9, and caspase-3 expression rose; however, hUCMSCs treatment reduced their expression. In addition, DIM-C-pPhOH had no effect on the NR4A1 expression, but it did increase the expression of apoptosis-related factors such as Bax, cytc, caspase-9, and caspase-3, causing the apoptosis of TICs.

Conclusions
These data show that hUCMSCs therapy improves ovarian function in POI rats by inhibiting TICs apoptosis through regulating NR4A1 -mediated mitochondrial mechanisms.
Concentrations of oocyte secreted GDF9 and BMP15 decrease with MII transition during human IVM
Authors: Cadenas Jesús , Pors Susanne Elisabeth , Kumar Ajay , Kalra Bhanu , Kristensen Stine Gry , Andersen Claus Yding , Mamsen Linn Salto 
Published: August 2022

Abstract
Background
The suggested effects of the oocyte secreted GDF9 and BMP15 growth factors on oocyte maturation are currently based on recombinant proteins, and little is known about native GDF9 and BMP15 in humans.

Methods
Human immature cumulus-oocyte complexes (COCs) obtained in connection with ovarian tissue cryopreservation (OTC) underwent in vitro maturation (IVM). Oocyte-produced GDF9 and BMP15 were detected in COCs using immunofluorescence, and in fresh GV oocytes and in GV and MII oocytes after IVM by western blot. Concentrations of GDF9, BMP15 homodimers, and GDF9/BMP15 heterodimer in spent media after IVM were measured by ELISA. The relative expression of seven genes from the GDF9 and BMP15 signaling pathways (BMPR2, ALK5, ALK6, SMAD1, SMAD2, SMAD3, and SMAD5) was evaluated in fresh cumulus cells (before IVM) and in cumulus cells from GV and MII oocytes after IVM by RT-qPCR.

Results
We detected native pro-mature GDF9 and BMP15 in human oocytes with molecular weights (Mw) of 47 kDa and 43 kDa, respectively. Concentrations of GDF9 and BMP15 in spent media after IVM were detected in 99% and 64% of the samples, respectively. The GDF9/BMP15 heterodimer was detected in 76% of the samples. Overall, the concentration of GDF9 was approximately 10-times higher than BMP15. The concentrations of both GDF9 and BMP15 were significantly lower in spent medium from MII oocytes than in media from oocytes that remained at the GV stage. Concentrations of the GDF9/BMP15 heterodimer did not differ between GV and MII oocytes. Furthermore, BMPR2, SMAD3, and SMAD5 were significantly upregulated in cumulus cells from MII oocytes, indicating that both GDF9 and BMP15 signaling were active during oocyte meiotic resumption in vitro.

Conclusion
These data suggest that the driving mechanisms for oocyte nuclear maturation may involve both GDF9 and BMP15 homodimers, while the role of the GDF9/BMP15 heterodimer is questionable.
Assessing the mental effects of COVID-19-related work on depression among community health workers in Vietnam
Authors: Hoang Ngoc-Anh , Van Hoang Ngoc , Quach Ha-Linh , Nguyen Khanh Cong , Duong Luong Huy , Pham Thai Quang , Vogt Florian 
Published: August 2022

Abstract
Background
Community health workers (CHWs) involved in the COVID-19 response might be at increased risk of developing depression, though evidence is scarce. We investigated effects of COVID-19-related work on changes in depression levels among CHWs in Vietnam and identified sub-groups among CHWs who are at particular risk of developing severe depression.

Methods
We conducted a cross-sectional online survey among 979 CHWs who were involved in the COVID-19 response in Vietnam, in particular during the 2021 Tet holiday outbreak between January and March 2021. Respondents were asked to report depression symptoms at two-time points, before the start of the COVID-19 pandemic (average June to December 2019) and during the 2021 Tet holiday outbreak using the PHQ-9 mental health questionnaire. We estimated depression levels at both time points and developed univariate and multivariable logistic regression models to estimate odds ratios and 95% confidence intervals (95% CIs) to explore the association between deterioration to high depression levels and selected risk factors.

Results
Median depression levels among CHWs in Vietnam doubled from 3 (IQR = 2–7) before COVID-19 to 6 (IQR = 3–9) on the PHQ-9 scale during the Tet holiday outbreak. The proportion with normal/minimal levels decreased from 77.1% (95% CI = 74.4–79.7) to 50.9% (95% CI = 47.7–54) (p-value < 0.001), while the proportion of CHWs with moderate, moderately severe, and severe depression levels increased 4.3, 4.5, and five-fold, respectively. Less sleep and poor sleep quality, working in unfavorable work environments, and being involved in contact tracing and the organization of quarantine for suspected cases were associated with an increased risk of deterioration to high depression levels.

Conclusions
We found a substantial increase in overall depression levels among CHWs in Vietnam due to their COVID-19 related work and a particularly worrisome rise in CHWs suffering from severe depression. CHWs are an indispensable yet often overlooked cadre of work in many low- and middle-income countries and shoulder a heavy psychological burden during the COVID-19 pandemic. Targeted psychological support for CHWs is needed to improve their mental health and to ensure the sustainability of community-based health interventions during COVID-19 and future epidemics.
Semaphorin3f as a cardiomyocyte derived regulator of heart chamber development
Authors: Halabi Rami , Cechmanek Paula Bernice , Hehr Carrie Lynn , McFarlane Sarah 
Published: August 2022

Abstract
Background
During development a pool of precursors form a heart with atrial and ventricular chambers that exhibit distinct transcriptional and electrophysiological properties. Normal development of these chambers is essential for full term survival of the fetus, and deviations result in congenital heart defects. The large number of genes that may cause congenital heart defects when mutated, and the genetic variability and penetrance of the ensuing phenotypes, reveals a need to understand the molecular mechanisms that allow for the formation of chamber-specific cardiomyocyte differentiation.

Methods
We used in situ hybridization, immunohistochemistry and functional analyses to identify the consequences of the loss of the secreted semaphorin, Sema3fb, in the development of the zebrafish heart by using two sema3fb CRISPR mutant alleles.

Results
We find that in the developing zebrafish heart sema3fb mRNA is expressed by all cardiomyocytes, whereas mRNA for a known receptor Plexina3 (Plxna3) is expressed preferentially by ventricular cardiomyocytes. In sema3fb CRISPR zebrafish mutants, heart chamber development is impaired; the atria and ventricles of mutants are smaller in size than their wild type siblings, apparently because of differences in cell size and not cell numbers. Analysis of chamber differentiation indicates defects in chamber specific gene expression at the border between the ventricular and atrial chambers, with spillage of ventricular chamber genes into the atrium, and vice versa, and a failure to restrict specialized cardiomyocyte markers to the atrioventricular canal (AVC). The hypoplastic heart chambers are associated with decreased cardiac output and heart edema.

Conclusions
Based on our data we propose a model whereby cardiomyocytes secrete a Sema cue that, because of spatially restricted expression of the receptor, signals in a ventricular chamber-specific manner to establish a distinct border between atrial and ventricular chambers that is important to produce a fully functional heart.
Poly(ADP-ribosyl)ation of acetyltransferase NAT10 by PARP1 is required for its nucleoplasmic translocation and function in response to DNA damage
Authors: Liu Hong-Yi , Liu Ying-Ying , Zhang Yin-Ling , Ning Yan , Zhang Fang-Lin , Li Da-Qiang 
Published: August 2022

Abstract
Background
N-acetyltransferase 10 (NAT10), an abundant nucleolar protein with both lysine and RNA cytidine acetyltransferase activities, has been implicated in Hutchinson-Gilford progeria syndrome and human cancer. We and others recently demonstrated that NAT10 is translocated from the nucleolus to the nucleoplasm after DNA damage, but the underlying mechanism remains unexplored.

Methods
The NAT10 and PARP1 knockout (KO) cell lines were generated using CRISPR-Cas9 technology. Knockdown of PARP1 was performed using specific small interfering RNAs targeting PARP1. Cells were irradiated with γ-rays using a 137Cs Gammacell-40 irradiator and subjected to clonogenic survival assays. Co-localization and interaction between NAT10 and MORC2 were examined by immunofluorescent staining and immunoprecipitation assays, respectively. PARylation of NAT10 and translocation of NAT10 were determined by in vitro PARylation assays and immunofluorescent staining, respectively.

Results
Here, we provide the first evidence that NAT10 underwent covalent PARylation modification following DNA damage, and poly (ADP-ribose) polymerase 1 (PARP1) catalyzed PARylation of NAT10 on three conserved lysine (K) residues (K1016, K1017, and K1020) within its C-terminal nucleolar localization signal motif (residues 983–1025). Notably, mutation of those three PARylation residues on NAT10, pharmacological inhibition of PARP1 activity, or depletion of PARP1 impaired NAT10 nucleoplasmic translocation after DNA damage. Knockdown or inhibition of PARP1 or expression of a PARylation-deficient mutant NAT10 (K3A) attenuated the co-localization and interaction of NAT10 with MORC family CW-type zinc finger 2 (MORC2), a newly identified chromatin-remodeling enzyme involved in DNA damage response, resulting in a decrease in DNA damage-induced MORC2 acetylation at lysine 767. Consequently, expression of a PARylation-defective mutant NAT10 resulted in enhanced cellular sensitivity to DNA damage agents.

Conclusion
Collectively, these findings indicate that PARP1-mediated PARylation of NAT10 is key for controlling its nucleoplasmic translocation and function in response to DNA damage. Moreover, our findings provide novel mechanistic insights into the sophisticated paradigm of the posttranslational modification-driven cellular response to DNA damage.
Opposing roles of CLK SR kinases in controlling HIV-1 gene expression and latency
Authors: Dahal Subha , Clayton Kiera , Been Terek , Fernet-Brochu Raphaële , Ocando Alonso Villasmil , Balachandran Ahalya , Poirier Mikaël , Maldonado Rebecca Kaddis , Shkreta Lulzim , Boligan Kayluz Frias , Guvenc Furkan , Rahman Fariha , Branch Donald , Bell Brendan , Chabot Benoit , Gray-Owen Scott D. , Parent Leslie J. , Cochrane Alan 
Published: August 2022

Abstract
Background
The generation of over 69 spliced HIV-1 mRNAs from one primary transcript by alternative RNA splicing emphasizes the central role that RNA processing plays in HIV-1 replication. Control is mediated in part through the action of host SR proteins whose activity is regulated by multiple SR kinases (CLK1-4, SRPKs).

Methods
Both shRNA depletion and small molecule inhibitors of host SR kinases were used in T cell lines and primary cells to evaluate the role of these factors in the regulation of HIV-1 gene expression. Effects on virus expression were assessed using western blotting, RT-qPCR, and immunofluorescence.

Results
The studies demonstrate that SR kinases play distinct roles; depletion of CLK1 enhanced HIV-1 gene expression, reduction of CLK2 or SRPK1 suppressed it, whereas CLK3 depletion had a modest impact. The opposing effects of CLK1 vs. CLK2 depletion were due to action at distinct steps; reduction of CLK1 increased HIV-1 promoter activity while depletion of CLK2 affected steps after transcript initiation. Reduced CLK1 expression also enhanced the response to several latency reversing agents, in part, by increasing the frequency of responding cells, consistent with a role in regulating provirus latency. To determine whether small molecule modulation of SR kinase function could be used to control HIV-1 replication, we screened a GSK library of protein kinase inhibitors (PKIS) and identified several pyrazolo[1,5-b] pyridazine derivatives that suppress HIV-1 gene expression/replication with an EC50 ~ 50 nM. The compounds suppressed HIV-1 protein and viral RNA accumulation with minimal impact on cell viability, inhibiting CLK1 and CLK2 but not CLK3 function, thereby selectively altering the abundance of individual CLK and SR proteins in cells.

Conclusions
These findings demonstrate the unique roles played by individual SR kinases in regulating HIV-1 gene expression, validating the targeting of these functions to either enhance latency reversal, essential for “Kick-and-Kill” strategies, or to silence HIV protein expression for “Block-and-Lock” strategies.
Awareness of pubertal body changes among primary school children aged 10–14 years in Eastern Uganda; challenges and opportunities
Authors: Bunoti Sarah Nantono , Tumwesigye Nazarius Mbona , Atuyambe Lynn 
Published: August 2022

Abstract
Background
Globally, programs that educate young people about pubertal body changes are vital. In some communities, teaching sexual education in schools has been the subject of debate. This is probably why access to sexual and reproductive health information and resources is still a challenge to children aged 10–14 years.

Methods
We conducted a qualitative study design among school children aged 10–14 years. Data were collected from 19 focus group discussions (FGDs) in 16 primary schools purposively selected from Eastern Uganda. Data were transcribed, coded and thematically analysed.

Results
We established that girls in rural schools were aware of their body changes than those from urban schools. Boys in urban schools were knowledgeable of pubertal body changes than those from rural schools. We further found that girls experienced pubertal-related challenges amongst themselves and boys including lack of shavers, pain while shaving, rape, bad boy–girl relationships, unwanted early pregnancies, limited funds to buy pads, menstrual pain, etc. Boys too indicated that they experienced similar challenges and these included lack of shavers, pain during and after shaving, changes in height, raping of girls, bad boy–girl relationships, peer pressure, HIV and other STIs, limited infrastructure, voice changes, bad body odour etc. Girls and boys endeavoured to overcome pubertal-related challenges by utilising advise from teachers, parents and friends.

Conclusion
Boys and girls who were knowledgeable about puberty body changes possessed opportunities that enable them to cope with pubertal-related challenges.
Barriers and facilitators to exclusive breastfeeding in rural Pakistan: a qualitative exploratory study
Authors: Riaz Atif , Bhamani Shelina , Ahmed Sheraz , Umrani Fayaz , Jakhro Sadaf , Qureshi Abdul Khaliq , Ali Syed Asad 
Published: August 2022

Abstract
Background
Exclusive breastfeeding (EBF) of children until six months of age is considered one of the most critical interventions in tackling childhood undernutrition. EBF rates are suboptimal in Pakistan, particularly in rural areas where child undernutrition is most prevalent. This study aimed to explore barriers to EBF in a rural context of Pakistan.

Methods
The study was conducted in the rural district Matiari of Sindh, Pakistan, during Jan-March 2020. We used a qualitative exploratory study design and conducted 36 focus group discussions (FGDs). Participants were purposively selected mothers who had not practiced EBF during their previous childbirth, their spouses and mothers-in-law, and lady health workers (LHWs) serving in the study catchment. FGDs were audio-recorded, transcribed, and translated into English from the local language and analysed using thematic content analysis.

Results
Barriers to EBF included low awareness and cultural practices of prelacteal feeds, insufficient breast milk production, undernutrition of mothers, mothers’ occupation as fieldworkers, less birth spacing, low awareness about the correct technique of breastfeeding, maternal and child ailments, abnormal breasts, and influence of in-laws to start top-up feeds. Several facilitators were identified: family support, appropriate maternal diet, maternal awareness, and support in the neighborhood.

Conclusion
Barriers to EBF are multifaceted in rural areas, and interventions aiming to improve adherence to EBFshould be multipronged. Awareness-raising alone might not be sufficient, and other interventions should be designed to address the barriers of maternal malnutrition, insufficient milk production, and socio-cultural practices. In addition, safe alternatives to breast milk may be necessary if breastfeeding is truly not feasible. Lack of breast milk substitutes is particularly challenging for poor rural women who cannot afford infant formula milk.