bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient reported outcomes following whole brain radiotherapy in patients with brain metastases in NSIA-LUTH Cancer Center
Authors: Adegboyega Bolanle , Joseph Adedayo , Alabi Adewumi , Omomila John , Ngema Lindokuhle M. , Ainsworth Victoria , Chin Jennifer , Evbuomwan Moses O , Ngwa Wilfred
Published: December 2023

Background

Brain metastases (BM) are a common complication in advanced cancer patients, and extremely challenging to treat. Consequently, whole brain radiotherapy (WBRT) remains the standard palliative intervention for patients with BM. The present study set to evaluate the clinical benefits of WBRT by assessing the quality of life (QoL) in WBRT-treated patients with BM, in Nigeria.

Methods

This was a prospective, longitudinal, hospital-based single-centre study. Consecutive sampling methodology was used to recruit 52 patients with BM undergoing WBRT. Patients were followed up on days 7, 30, 90 and 180 after WBRT. The EORTC QLQ-C15-PAL and EORTC QLQ-BN20 were employed to report patients’ responses. The likert scale responses were linearly converted into 0 – 100 scores, and the descriptive analysis was conducted using IBM SPSS Statistics 29.0, at 95% confidence interval, using the two-tailed t-test for continuous variables or the chi-square test for categorical values. The overall survival was calculated with the Kaplan Maier method and the difference tested with Log-rank method, considering the interval from the baseline until death or end of the study.

Results

The study cohort was predominantly females (82.7%), and accordingly, 65.4% of the respondents had a breast primary tumor. A goodness-of-fit test yielded non-significant Chi square Pearson (p = 0.325) and Deviance (p = 1.000) residuals, indicating the best fit. The median overall survival was 180 days (~ 6 months). A total of 20 patients (38%) that survived up to 180 days reported alleviated symptoms and better functioning. A significant improvement in physical functioning (p < 0.001) and emotional functioning (p = 0.031) was reported at 180 days post WBRT, compared to baseline.

Conclusions

WBRT is an effective palliative intervention in patients with BM, resulting in improved QoL. More than 50% of patients that survived ~ 3 months reported alleviation of pain, and 38% of patients that survived for ~ 6 months reported a significantly improved functioning. This demonstrated the clinical benefits of WBRT in palliative care and will add to the body of data on the use of WBRT, from Africa.
Cellular senescence contributes to mechanical ventilation-induced diaphragm dysfunction by upregulating p53 signalling pathways
Authors: Shen Weimin , Jiang Ye , Xu Ying , Qian Xiaoli , Jia Jianwei , Ding Yuejia , He Yuhan , Pan Qing , Zhuang Jinyang , Ge Huiqing , Xu Peifeng
Published: December 2023

Background

Mechanical ventilation can cause acute atrophy and injury in the diaphragm, which are related to adverse clinical results. However, the underlying mechanisms of ventilation-induced diaphragm dysfunction (VIDD) have not been well elucidated. The current study aimed to explore the role of cellular senescence in VIDD.

Methods

A total of twelve New Zealand rabbits were randomly divided into 2 groups: (1) spontaneously breathing anaesthetized animals (the CON group) and (2) mechanically ventilated animals (for 48 h) in V-ACV mode (the MV group). Respiratory parameters were collected during ventilation. Diaphragm were collected for further analyses.

Results

Compared to those in the CON group, the percentage and density of sarcomere disruption in the MV group were much higher (p < 0.001, both). The mRNA expression of MAFbx and MuRF1 was upregulated in the MV group (p = 0.003 and p = 0.006, respectively). Compared to that in the CON group, the expression of MAFbx and MuRF1 detected by western blotting was also upregulated (p = 0.02 and p = 0.03, respectively). Moreover, RNA-seq showed that genes associated with senescence were remarkably enriched in the MV group. The mRNA expression of related genes was further verified by q-PCR (Pai1: p = 0.009; MMP9: p = 0.008). Transverse cross-sections of diaphragm myofibrils in the MV group showed more intensive positive staining of SA-βGal than those in the CON group. p53-p21 axis signalling was elevated in the MV group. The mRNA expression of p53 and p21 was significantly upregulated (p = 0.02 and p = 0.05, respectively). The western blot results also showed upregulation of p53 and p21 protein expression (p = 0.03 and p = 0.05, respectively). Moreover, the p21-positive staining in immunofluorescence and immunohistochemistry in the MV group was much more intense than that in the CON group (p < 0.001, both).

Conclusions

In a rabbit model, we demonstrated that mechanical ventilation in A/C mode for 48 h can still significantly induce ultrastructural damage and atrophy of the diaphragm. Moreover, p53-dependent senescence might play a role in mechanical ventilation-induced dysfunction. These findings might provide novel therapeutic targets for VIDD.
No difference in patient reported outcome and inflammatory response after coated and uncoated total knee arthroplasty – a randomized controlled study
Authors: Tille Eric , Beyer Franziska , Lützner Cornelia , Postler Anne , Thomas Peter , Summer Burkhard , Lützner Jörg
Published: December 2023

Background

Allergies against implant materials are still not fully understood. Despite controversies about its relevance, some patients need treatment with hypoallergenic implants. This study compared coated and standard total knee arthroplasty (TKA) regarding inflammatory response and patient-reported outcome measures (PROMs).

Methods

76 patients without self-reported allergies against implant materials were included in a RCT and received a coated or standard TKA of the same cemented posterior-stabilized knee system. 73 patients completed the 3-year follow-up. Two patients died and there was one revision surgery. Serum levels of cytokines with a possible role in implant allergy were measured in patient`s serum (IL-1beta, IL-5, IL-6, IL-8, IL-10, IFN γ, TNF α) prior to, one and three years after surgery. Furthermore, PROMs including knee function (Oxford Knee Score, Knee Society Score) and health-related quality of life (QoL, EuroQuol questionnaire) were assessed. Additionally, 8 patients with patch-test proven skin allergy against implant materials who received the coated implant were assessed similarly and compared to a matched-pair group receiving the same implant.

Results

There were no differences in function and QoL between the assessed groups at any follow-up. The majority of patients demonstrated no elevation of the measured blood cytokines. Cytokine patterns showed no differences between study groups at any follow-up. The allergy patients demonstrated slower functional improvement and minor differences in cytokine pattern. Yet these results were not significant. There were no differences in the matched-pair analysis.

Conclusion

We observed no relevant increase in serum cytokine levels in any group. The inflammatory response measured seems limited, even in allergy patients. Furthermore, there were no differences between coated and standard TKA in non-allergy patients in the 3-year Follow-Up period.

Trial registration

The study protocol was registered in the US National Institutes of Health’s database (http://www.clinicaltrials.gov) registry under NCT03424174 on 03/17/2016.
Resorbable magnesium metal membrane for sinus lift procedures: a case series
Authors: Elad Akiva , Pul Luka , Rider Patrick , Rogge Svenja , Witte Frank , Tadić Dražen , Mijiritsky Eitan , Kačarević Željka Perić , Steigmann Larissa
Published: December 2023

Background

The purpose of this case series was to demonstrate the use of a magnesium membrane for repairing the perforated membrane in both direct and indirect approaches, as well as its application in instances where there has been a tear of the Schneiderian membrane.

Case presentation

The case series included four individual cases, each demonstrating the application of a magnesium membrane followed by bone augmentation using a mixture of xenograft and allograft material in the sinus cavity. In the first three cases, rupture of Schneiderian membrane occurred as a result of tooth extraction, positioning of the dental implant, or as a complication during the procedure. In the fourth case, Schneiderian membrane was perforated as a result of the need to aspirate a polyp in the maxillary sinus. In case one, 10 mm of newly formed bone is visible four months after graft placement. Other cases showed between 15 and 20 mm of newly formed alveolar bone. No residual magnesium membrane was seen on clinical inspection. The vertical and horizontal augmentations proved stable and the dental implants were placed in the previously grafted sites.

Conclusion

Within the limitations of this case series, postoperative clinical examination, and panoramic and CBCT images demonstrated that resorbable magnesium membrane is a viable material for sinus lift and Schneiderian membrane repair. The case series showed successful healing and formation of new alveolar bone with separation of the oral cavity and maxillary sinus in four patients.
Survival rate of cervical cancer in Asian countries: a systematic review and meta-analysis
Authors: Vali Mohebat , Maleki Zahra , Nikbakht Hossein-Ali , Hassanipour Soheil , Kouhi Aida , Nazemi Sina , hajizade-valokolaee Maryam , Nayeb MohammadReza , Ghaem Haleh
Published: December 2023

Objective

Cancer is one of the main causes of death, and cervical cancer is the fourth most common cancer and the fourth leading cause of death from malignancy among women. Knowing the survival rate is used to evaluate the success of current treatments and care. This study was conducted to assess the survival rate of cervical cancer in Asia.

Methods

This systematic survey was conducted on four international databases, including Medline/PubMed, ProQuest, Scopus, and Web of Knowledge, and includes manuscripts that were published until the end of August 2021. Selected keywords were searched for international databases including cervical neoplasms [mesh], survival analysis or survival or survival rate, Asian countries (name of countries). The Newcastle-Ottawa Qualitative Evaluation Form was used for cohort studies to evaluate the quality of the articles. The analysis process was performed to evaluate the heterogeneity of the studies using the Cochran test and I2 statistics. Additionally, a meta-regression analysis was performed based on the year of the study.

Results

A total of 1956 articles were selected and reviewed based on their title. The results showed that 110 articles met the inclusion criteria. According to the randomized model, the 1, 3, 5, and 10-year survival rates of cervical cancer were 76.62% (95% Confidence Interval (CI), 72.91_80.34), 68.77% (95% CI, 64.32_73.21), 62.34% (95% CI, 58.10_66.59), and 61.60% (95% CI, 52.31_70.89), respectively. Additionally, based on the results of meta-regression analysis, there was an association between the year of the study and the survival rate, elucidating that the survival rate of cervical cancer has increased over the years.

Conclusions

Results can provide the basic information needed for effective policy making, and development of public health programs for prevention, diagnosis, and treatment of cervical cancer.
Construction and evaluation of a column chart model and a random forest model for predicting the prognosis of hydrodistention surgery in BPS/IC patients based on preoperative CD117, P2X3R, NGF, and TrkA levels
Authors: Pang Lei , Ding Zijun , Chai Hongqiang , Shuang Weibing
Published: December 2023

Objective

This study seeks to investigate independent risk factors affecting the prognoses of patients with bladder pain syndrome/interstitial cystitis (BPS/IC) following hydrodistention surgery and to develop a column chart model and a random forest model to help predict clinical outcomes.

Method

A retrospective analysis was conducted on the clinical data of 1006 BPS/IC patients who visited the urology department of the Fifth Hospital of Shanxi Medical University (Shanxi Provincial People's Hospital) between June 2012 and June 2022. The patients were randomly divided into a model group (n = 704) and a validation group (n = 302). In the model group, logistic regression analysis was used to identify independent risk factors, which were used to construct a prognostic nomogram. The nomogram was evaluated by analyzing the area under the curve (AUC), calibration curve, and decision curve. These results were subsequently validated via consistency analysis (n = 302). And based on the random forest algorithm, we calculate the same data and construct a random forest model.

Result

Multivariate logistic regression analysis revealed that age and the expression of the biomarkers CD117, P2X3R, NGF, and TrkA were independent prognostic factors for patients with BPS/IC (P < 0.05). Using these five indicators, a nomogram was developed to predict the risk factors for BPS/IC (scores ranged from 0 to 400). Based on the indicators, the nomogram demonstrated good prognostic performance (AUC = 0.982 and 95% confidence interva is 0.960–0.100). The correction curve indicated a high level of differentiation in the model, and the decision curve suggested positive clinical benefits. The random forest model has high accuracy and good calibration in predicting the prognosis of patients with interstitial cystitis after hydrodistention surgery.

Conclusion

Age, CD117, P2X3R, NGF, and TrkA are independent prognostic factors for bladder pain syndrome/interstitial cystitis. The column chart model and random forest model constructed based on these indicators have good predictive performance for patient prognosis.
“I am not just a place for implementation. I should be a partner”: a qualitative study of patient-centered care from the perspective of diabetic patients in Saudi Arabia
Authors: Alkhaibari Reeham Ahmed , Smith-Merry Jennifer , Forsyth Rowena
Published: December 2023

Introduction

Patient involvement in care is a major component of high quality of care and is becoming recognized worldwide with many beneficial for improving patient outcomes. However, a little is known about patient involvement in the Middle East region and Saudi Arabia in particular.

Objectives

To evaluate patients’ perceptions of their involvement during their interactions with healthcare providers in Saudi Arabia.

Methods

A qualitative exploratory study using semi structured interview was conducted from February 2022 to March 2022. Responses were transcribed and analyzed using a thematic analysis approach.

Results

We conducted seven interviews with patients with diabetes ranging in age from 19 to 69 years old. We identified the following themes:1) patients’ perceptions of their involvement in care, 2) barriers to patient involvement, 3) effective communication, 4) empathy, and 5) culture. We found that patients had minimal knowledge of patient involvement in care.

Conclusion

There is a clear need to improve education and awareness of patient involvement in Saudi Arabia. By educating patients about the possibilities of patient involvement and explaining their role it will make it easier for patients to understand appropriate levels of involvement. In addition, there is a need to understand the patient-centred care culture in Saudi Arabia through establishing frameworks with the focus on culture and patient-centred healthcare delivery.
The effect of internal salary incentives based on insurance payment on physicians’ behavior: experimental evidence
Authors: Li Xing , Teng Jiali , Li Xinyan , Lin Xing , Han Youli
Published: December 2023

Background

Understanding how physicians respond to payment methods is crucial for designing effective incentives and enhancing the insurance system. Previous theoretical research has explored the effects of payment methods on physician behavior based on a two-level incentive path; however, empirical evidence to validate these theoretical frameworks is lacking. To address this research gap, we conducted a laboratory experiment to investigate physicians’ behavioral responses to three types of internal salary incentives based on diagnosis-related-group (DRG) and fee-for-service (FFS).

Methods

A total of 150 medical students from Capital Medical University were recruited as participants. These subjects played the role of physicians in choosing the quantity of medical services for nine types of patients under three types of salary incentives—fixed wage, constant fixed wage with variable performance wage, and variable fixed wage with variable performance wage, of which performance wage referred to the payment method balance under FFS or DRG. We collected data on the quantities of medical services provided by the participants and analyzed the results using the Friedman test and the fixed effects model.

Results

The results showed that a fixed wage level did not have a significant impact on physicians’ behavior. However, the patients benefited more under the fixed wage compared to other salary incentives. In the case of a floating wage system, which consisted of a constant fixed wage and a variable performance wage from the payment method balance, an increase in performance wage led to a decrease in physicians’ service provision under DRG but an increase under FFS. Consequently, this resulted in a decrease in patient benefit. When the salary level remained constant, but the composition of the salary varied, physicians’ behavior changed slightly under FFS but not significantly under DRG. Additionally, patient benefits decreased as the ratio of performance wages increased under FFS.

Conclusions

While using payment method balance as physicians’ salary may be effective in transferring incentives of payment methods to physicians through internal compensation frameworks, it should be used with caution, particularly when the measurement standard of care is imperfect.
Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines
Authors: Rickard Brittany P. , Overchuk Marta , Tulino Justin , Tan Xianming , Ligler Frances S. , Bae-Jump Victoria L. , Fenton Suzanne E. , Rizvi Imran
Published: December 2023

Background

Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease.

Objectives

To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer.

Methods

HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment.

Results

HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment.

Discussion

Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.
Cardiac imaging in athlete’s heart: current status and future prospects
Authors: Zholshybek Nurmakhan , Khamitova Zaukiya , Toktarbay Bauyrzhan , Jumadilova Dinara , Khissamutdinov Nail , Dautov Tairkhan , Rakhmanov Yeltay , Bekbossynova Makhabbat , Gaipov Abduzhappar , Salustri Alessandro
Published: December 2023

Background

Physical activity contributes to changes in cardiac morphology, which are known as “athlete’s heart”. Therefore, these modifications can be characterized using different imaging modalities such as echocardiography, including Doppler (flow Doppler and Doppler myocardial imaging) and speckle-tracking, along with cardiac magnetic resonance, and cardiac computed tomography.

Main text

Echocardiography is the most common method for assessing cardiac structure and function in athletes due to its availability, repeatability, versatility, and low cost. It allows the measurement of parameters like left ventricular wall thickness, cavity dimensions, and mass.

Left ventricular myocardial strain can be measured by tissue Doppler (using the pulse wave Doppler principle) or speckle tracking echocardiography (using the two-dimensional grayscale B-mode images), which provide information on the deformation of the myocardium.

Cardiac magnetic resonance provides a comprehensive evaluation of cardiac morphology and function with superior accuracy compared to echocardiography. With the addition of contrast agents, myocardial state can be characterized. Thus, it is particularly effective in differentiating an athlete’s heart from pathological conditions, however, is less accessible and more expensive compared to other techniques.

Coronary computed tomography is used to assess coronary artery anatomy and identify anomalies or diseases, but its use is limited due to radiation exposure and cost, making it less suitable for young athletes.

A novel approach, hemodynamic forces analysis, uses feature tracking to quantify intraventricular pressure gradients responsible for blood flow. Hemodynamic forces analysis has the potential for studying blood flow within the heart and assessing cardiac function.

Conclusions

In conclusion, each diagnostic technique has its own advantages and limitations for assessing cardiac adaptations in athletes. Examining and comparing the cardiac adaptations resulting from physical activity with the structural cardiac changes identified through different diagnostic modalities is a pivotal focus in the field of sports medicine.

Graphical Abstract
YAP-mediated trophoblast dysfunction: the common pathway underlying pregnancy complications
Authors: Lin Qimei , Cao Jiasong , Yu Jing , Zhu Yu , Shen Yongmei , Wang Shuqi , Wang Yixin , Liu Zhen , Chang Ying
Published: December 2023

Yes-associated protein (YAP) is a pivotal regulator in cellular proliferation, survival, differentiation, and migration, with significant roles in embryonic development, tissue repair, and tumorigenesis. At the maternal–fetal interface, emerging evidence underscores the importance of precisely regulated YAP activity in ensuring successful pregnancy initiation and progression. However, despite the established association between YAP dysregulation and adverse pregnancy outcomes, insights into the impact of aberrant YAP levels in fetal-derived, particularly trophoblast cells, and the ensuing dysfunction at the maternal–fetal interface remain limited. This review comprehensively examines YAP expression and its regulatory mechanisms in trophoblast cells throughout pregnancy. We emphasize its integral role in placental development and maternal–fetal interactions and delve into the correlations between YAP dysregulation and pregnancy complications. A nuanced understanding of YAP's functions during pregnancy could illuminate intricate molecular mechanisms and pave the way for innovative prevention and treatment strategies for pregnancy complications.
Caregiver-child interaction as an effective tool for identifying autism spectrum disorder: evidence from EEG analysis
Authors: Deng Lin , He Wei-zhong , Zhang Qing-li , Wei Ling , Dai Yuan , Liu Yu-qi , Chen Zi-lin , Ren Tai , Zhang Lin-li , Gong Jing-bo , Li Fei
Published: December 2023

Background

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that affects individuals across their lifespan. Early diagnosis and intervention are crucial for improving outcomes. However, current diagnostic methods are often time-consuming, and costly, making them inaccessible to many families. In the current study, we aim to test caregiver-child interaction as a potential tool for screening children with ASD in clinic.

Methods

We enrolled 85 preschool children (Mean age: 4.90 ± 0.65 years, 70.6% male), including ASD children with or without developmental delay (DD), and typical development (TD) children, along with their caregivers. ASD core symptoms were evaluated by Childhood Autism Rating Scale (CARS) and Autism Diagnostic Observation Schedule-Calibrated Severity Scores (ADOS-CSS). Behavioral indicators were derived from video encoding of caregiver-child interaction, including social involvement of children (SIC), interaction time (IT), response of children to social cues (RSC), time for caregiver initiated social interactions (GIS) and time for children initiated social interactions (CIS)). Power spectral density (PSD) values were calculated by EEG signals simultaneously recorded. Partial Pearson correlation analysis was used in both ASD groups to investigate the correlation among behavioral indicators scores and ASD symptom severity and PSD values. Receiver operating characteristic (ROC) analysis was used to describe the discrimination accuracy of behavioral indicators.

Results

Compared to TD group, both ASD groups demonstrated significant lower scores of SIC, IT, RSC, CIS (all p values < 0.05), and significant higher time for GIS (all p values < 0.01). SIC scores negatively correlated with CARS (p = 0.006) and ADOS-CSS (p = 0.023) in the ASD with DD group. Compared to TD group, PSD values elevated in ASD groups (all p values < 0.05), and was associated with SIC (theta band: p = 0.005; alpha band: p = 0.003) but not IQ levels. SIC was effective in identifying both ASD groups (sensitivity/specificity: ASD children with DD, 76.5%/66.7%; ASD children without DD, 82.6%/82.2%).

Conclusion

Our results verified the behavioral paradigm of caregiver-child interaction as an efficient tool for early ASD screening.
Nutlin-3a induces KRAS mutant/p53 wild type lung cancer specific methuosis-like cell death that is dependent on GFPT2
Authors: Kim Dasom , Min Dongwha , Kim Joohee , Kim Min Jung , Seo Yerim , Jung Byung Hwa , Kwon Seung‑Hae , Ro Hyunju , Lee Seoee , Sa Jason K. , Lee Ji-Yun
Published: December 2023

Background

Oncogenic KRAS mutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-class KRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for other KRAS mutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies.

Methods

KRAS mutant, and wildtype NSCLC cells were used in vitro cell analyses. Cell viability, proliferation, and death were measured by MTT, cell counting, colony analyses, and annexin V staining for FACS. Cell tracker dyes were used to investigate cell morphology, which was examined by holotomograpy, and confocal microscopes. RNA sequencing was performed to identify key target molecule or pathway, which was confirmed by qRT-PCR, western blotting, and metabolite analyses by UHPLC-MS/MS. Zebrafish and mouse xenograft model were used for in vivo analysis.

Results

In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically in KRAS mutant /p53 wild type NSCLC cells.

Conclusion

These results indicate the potential of nutlin-3a as an alternative agent for treating KRAS mutant/p53 wild type NSCLC cells.
Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest
Authors: Wider Joseph M. , Gruley Erin , Morse Paul T. , Wan Junmei , Lee Icksoo , Anzell Anthony R. , Fogo Garrett M. , Mathieu Jennifer , Hish Gerald , O’Neil Brian , Neumar Robert W. , Przyklenk Karin , Hüttemann Maik , Sanderson Thomas H.
Published: December 2023

Background

Brain injury is a leading cause of morbidity and mortality in patients resuscitated from cardiac arrest. Mitochondrial dysfunction contributes to brain injury following cardiac arrest; therefore, therapies that limit mitochondrial dysfunction have the potential to improve neurological outcomes. Generation of reactive oxygen species (ROS) during ischemia–reperfusion injury in the brain is a critical component of mitochondrial injury and is dependent on hyperactivation of mitochondria following resuscitation. Our previous studies have provided evidence that modulating mitochondrial function with specific near-infrared light (NIR) wavelengths can reduce post-ischemic mitochondrial hyperactivity, thereby reducing brain injury during reperfusion in multiple small animal models.

Methods

Isolated porcine brain cytochrome c oxidase (COX) was used to investigate the mechanism of NIR-induced mitochondrial modulation. Cultured primary neurons from mice expressing mitoQC were utilized to explore the mitochondrial mechanisms related to protection with NIR following ischemia–reperfusion. Anesthetized pigs were used to optimize the delivery of NIR to the brain by measuring the penetration depth of NIR to deep brain structures and tissue heating. Finally, a model of out-of-hospital cardiac arrest with CPR in adult pigs was used to evaluate the translational potential of NIR as a noninvasive therapeutic approach to protect the brain after resuscitation.

Results

Molecular evaluation of enzyme activity during NIR irradiation demonstrated COX function was reduced in an intensity-dependent manner with a threshold of enzyme inhibition leading to a moderate reduction in activity without complete inhibition. Mechanistic interrogation in neurons demonstrated that mitochondrial swelling and upregulation of mitophagy were reduced with NIR treatment. NIR therapy in large animals is feasible, as NIR penetrates deep into the brain without substantial tissue heating. In a translational porcine model of CA/CPR, transcranial NIR treatment for two hours at the onset of return of spontaneous circulation (ROSC) demonstrated significantly improved neurological deficit scores and reduced histologic evidence of brain injury after resuscitation from cardiac arrest.

Conclusions

NIR modulates mitochondrial function which improves mitochondrial dynamics and quality control following ischemia/reperfusion. Noninvasive modulation of mitochondria, achieved by transcranial treatment of the brain with NIR, mitigates post-cardiac arrest brain injury and improves neurologic functional outcomes.

Graphical abstract
HER2 amplification level by in situ hybridization predicts survival outcome in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 IHC results
Authors: Seo Jeongmin , Koh Jiwon , Lee Dae-Won , Kim Jinyong , Ryu Han Suk , Lee Kyung-Hun , Kim Tae-Yong , Im Seock-Ah
Published: December 2023

Background

The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored.

Methods

This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH).

Results

A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p = 0.022) and OS (HR 0.28, p = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p < 0.001) and OS (HR 0.27, p = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p = 0.004) and potentially for OS (HR 0.64, p = 0.054), along with HER2 copy number (PFS HR 0.85, p = 0.004; OS HR 0.84, p = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories.

Conclusions

This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.
A dual-antigen malaria vaccine targeting Pb22 and Pbg37 was able to induce robust transmission-blocking activity
Authors: Gao Wenyan , Qiu Yue , Zhu Liying , Yu Xinxin , Yang Fan , Chen Muyan , He Gang , Liu Yinjie , Cui Liwang , Liu Fei , Zhu Xiaotong , Cao Yaming
Published: December 2023

Background

Despite years of effort to develop an effective vaccine against malaria infection, a vaccine that provides individuals with sufficient protection against malaria illness and death in endemic areas is not yet available. The development of transmission-blocking vaccines (TBVs) is a promising strategy for malaria control. A dual-antigen malaria vaccine targeting both pre- and post-fertilization antigens could effectively improve the transmission-blocking activity of vaccines against the sexual stages of the parasite.

Methods

A chimeric recombinant protein Pb22-Pbg37 (Plasmodium berghei 22-P. berghei G37) composed of 19–218 amino acids (aa) of Pb22 and the N-terminal 26–88 aa of Pbg37 was designed and expressed in the Escherichia coli expression system. The antibody titers of the fusion (Pb22-Pbg37) and mixed (Pb22+Pbg37) antigens, as well as those of Pb22 and Pbg37 single antigens were evaluated by enzyme-linked immunosorbent assay. Immunofluorescence and western blot assays were performed to test the reactivity of the antisera with the native proteins in the parasite. The induction of transmission-blocking activity (TBA) by Pb22-Pbg37 and Pb22+Pbg37 were evaluated by in vitro gametocyte activation, gamete and exflagellation center formation, ookinete conversion, and in the direct mosquito feeding assay.

Results

The Pb22-Pbg37 fusion protein was successfully expressed in vitro. Co-administration of Pb22 and Pbg37 as a fusion or mixed protein elicited comparable antibody responses in mice and resulted in responses to both antigens. Most importantly, both the mixed and fusion antigens induced antibodies with significantly higher levels of TBA than did each of the individual antigens when administered alone. In addition, the efficacy of vaccination with the Pb22-Pbg37 fusion protein was equivalent to that of vaccination with the mixed single antigens.

Conclusions

Dual-antigen vaccines, which expand/lengthen the period during which the transmission-blocking antibodies can act during sexual-stage development, can provide a promising higher transmission-reducing activity compared to single antigens.

Graphical Abstract
The secretome of Staphylococcus aureus strains with opposite within-herd epidemiological behavior affects bovine mononuclear cell response
Authors: Di Mauro Susanna , Filipe Joel , Facchin Alessia , Roveri Laura , Addis Maria Filippa , Monistero Valentina , Piccinini Renata , Sala Giulia , Pravettoni Davide , Zamboni Clarissa , Ceciliani Fabrizio , Lecchi Cristina
Published: December 2023

Staphylococcus aureus modulates the host immune response directly by interacting with the immune cells or indirectly by secreting molecules (secretome). Relevant differences in virulence mechanisms have been reported for the secretome produced by different S. aureus strains. The present study investigated the S. aureus secretome impact on peripheral bovine mononuclear cells (PBMCs) by comparing two S. aureus strains with opposite epidemiological behavior, the genotype B (GTB)/sequence type (ST) 8, associated with a high within-herd prevalence, and GTS/ST398, associated with a low within-herd prevalence. PBMCs were incubated with different concentrations (0%, 0.5%, 1%, and 2.5%) of GTB/ST8 and GTS/ST398 secretome for 18 and 48 h, and the viability was assessed. The mRNA levels of pro- (IL1-β and STAT1) and anti-inflammatory (IL-10, STAT6, and TGF-β) genes, and the amount of pro- (miR-155-5p and miR-125b-5p) and anti-inflammatory (miR-146a and miR-145) miRNAs were quantified by RT-qPCR. Results showed that incubation with 2.5% of GTB/ST8 secretome increased the viability of cells. In contrast, incubation with the GTS/ST398 secretome strongly decreased cell viability, preventing any further assays. The GTB/ST8 secretome promoted PBMC polarization towards the pro-inflammatory phenotype inducing the overexpression of IL1-β, STAT1 and miR-155-5p, while the expression of genes involved in the anti-inflammatory response was not affected. In conclusion, the challenge of PBMC to the GTS/ST398 secretome strongly impaired cell viability, while exposure to the GTB/ST8 secretome increased cell viability and enhanced a pro-inflammatory response, further highlighting the different effects exerted on host cells by S. aureus strains with epidemiologically divergent behaviors.
LINE-1 global DNA methylation, iron homeostasis genes, sex and age in sudden sensorineural hearing loss (SSNHL)
Authors: Tisato Veronica , Castiglione Alessandro , Ciorba Andrea , Aimoni Claudia , Silva Juliana Araujo , Gallo Ines , D’Aversa Elisabetta , Salvatori Francesca , Bianchini Chiara , Pelucchi Stefano , Secchiero Paola , Zauli Giorgio , Singh Ajay Vikram , Gemmati Donato
Published: December 2023

Background

Sudden sensorineural hearing loss (SSNHL) is an abrupt loss of hearing, still idiopathic in most of cases. Several mechanisms have been proposed including genetic and epigenetic interrelationships also considering iron homeostasis genes, ferroptosis and cellular stressors such as iron excess and dysfunctional mitochondrial superoxide dismutase activity.

Results

We investigated 206 SSNHL patients and 420 healthy controls for the following genetic variants in the iron pathway: SLC40A1 − 8CG (ferroportin; FPN1), HAMP − 582AG (hepcidin; HEPC), HFE C282Y and H63D (homeostatic iron regulator), TF P570S (transferrin) and SOD2 A16V in the mitochondrial superoxide dismutase-2 gene. Among patients, SLC40A1 − 8GG homozygotes were overrepresented (8.25% vs 2.62%; P = 0.0015) as well SOD2 16VV genotype (32.0% vs 24.3%; P = 0.037) accounting for increased SSNHL risk (OR = 3.34; 1.54–7.29 and OR = 1.47; 1.02–2.12, respectively). Moreover, LINE-1 methylation was inversely related (r2 = 0.042; P = 0.001) with hearing loss score assessed as pure tone average (PTA, dB HL), and the trend was maintained after SLC40A1 − 8CG and HAMP − 582AG genotype stratification (ΔSLC40A1 = + 8.99 dB HL and ΔHAMP = − 6.07 dB HL). In multivariate investigations, principal component analysis (PCA) yielded PC1 (PTA, age, LINE-1, HAMP, SLC40A1) and PC2 (sex, HFEC282Y, SOD2, HAMP) among the five generated PCs, and logistic regression analysis ascribed to PC1 an inverse association with moderate/severe/profound HL (OR = 0.60; 0.42–0.86; P = 0.0006) and with severe/profound HL (OR = 0.52; 0.35–0.76; P = 0.001).

Conclusion

Recognizing genetic and epigenetic biomarkers and their mutual interactions in SSNHL is of great value and can help pharmacy science to design by pharmacogenomic data classical or advanced molecules, such as epidrugs, to target new pathways for a better prognosis and treatment of SSNHL.
Is it now time to iron out the wrinkles? Health of Shar Pei dogs under primary veterinary care in the UK
Authors: O’Neill Dan G. , Engdahl Karolina S. , Leach Alice , Packer Rowena M. A. , Church David B. , Brodbelt Dave C.
Published: December 2023

Background

The Shar Pei is a common dog breed with a distinctive appearance caused by hyaluronosis that has been linked with several health conditions. Anonymised primary-care veterinary clinical records were explored to extract data on the demography, common disorders and mortality of Shar Pei in the UK in 2013.

Results

The study population of 455,557 dogs included 1913 (0.42%) Shar Pei. The mean adult bodyweight was 22.26 kg. The most prevalent fine-level precision disorders were entropion (prevalence 17.88%, 95% CI: 16.16-19.59), otitis externa (16.36%, 95% CI: 14.70-18.02), ear disorders (6.69%, 95% CI: 5.57-7.81), aggression (5.23%, 95% CI: 4.23-6.22), and pyoderma (4.29%, 95% CI: 3.38-5.19). The most prevalent disorder groups were ophthalmologic (prevalence = 22.27%, 95% CI: 20.40-24.13), dermatological (21.01%, 95% CI: 19.19-22.84), aural (18.66%, 95% CI: 16.92-20.41), traumatic injury (7.53%, 95% CI: 6.35-8.71) and behavioural (7.21%, 95% CI: 6.05-8.37). The median longevity of 190 Shar Pei that died during the study period was 7.28 years (IQR 5.04-10.05, range 0.04-15.04). Of 184 deaths with a recorded method of death, 157 (85.33%) deaths involved euthanasia and 27 (14.67%) deaths were unassisted. Among 136 (71.58%) deaths with a recorded biomedical cause of death, the most common causes of death at group level precision were neoplasia (15.44%, 95% CI: 9.37-21.51), renal disorders (13.24%, 95% CI: 7.54-18.93), and behavioural disorders (11.03%, 95% CI: 5.76-16.29).

Conclusions

Almost one fifth of Shar Pei receive veterinary care each year for entropion, a condition linked strongly with the extreme conformation of thickened and folded skin and bristly hair that characterises the Shar Pei breed. Several other common disorders are also linked to hyaluronosis. Current UK legislation can help support efforts to avoid breeding or acquiring animals with extreme conformations and to promote adequate veterinary care for already-owned animals with extreme conformations.
Climatology of mesosphere and lower thermosphere diurnal tides over Jicamarca (12$$^\circ$$S, 77$$^\circ$$W): observations and simulations
Authors: Suclupe Jose , Chau Jorge L. , Conte J. Federico , Milla Marco , Pedatella N. M. , Kuyeng K.
Published: December 2023

This work shows a 3-year climatology of the horizontal components of the solar diurnal tide, obtained from wind measurements made by a multistatic specular meteor radar (SIMONe) located in Jicamarca, Peru (12$$^\circ$$

∘

S, 77$$^\circ$$

∘

W). Our observations show that the meridional component is more intense than the zonal component, and that it exhibits its maxima shifted with respect to the equinox times (i.e., the largest peak occurs in August–September, and the second one in April–May). The zonal component only shows a clear maximum in August–September. This observational climatology is compared to a climatology obtained with the Whole Atmosphere Community Climate Model with thermosphere and ionosphere extension (WACCM-X). Average comparisons indicate that the model amplitudes are 50% smaller than the observed ones. The WACCM-X results are also used in combination with observed altitude profiles of the tidal phases to understand the relative contributions of migrating and non-migrating components. Based on this, we infer that the migrating diurnal tide (DW1) dominates in general, but that from June until September (November until July) the DE3 (DW2) may have a significant contribution to the zonal (meridional) component. Finally, applying wavelet analysis to the complex amplitude of the total diurnal tide, modulating periods between 5 and 80 days are observed in the SIMONe measurements and the WACCM-X model. These modulations might be associated to planetary waves and intraseasonal oscillations in the lower tropical atmosphere.

Graphical Abstract
Soilkin
Authors: Toland Alexandra Regan
Published: December 2023

Drawing on ideas from the history and philosophy of soil science, Fluxus performance, and queer-feminist STS, this article responds to a question posed by environmental researcher Hugo Reinert: “What modes of passionate immersion—or love, or intimacy—could a stone afford?” Situated in a fluid space between environmental humanities and artistic research, the Soilkin project develops a series of relational exercises to frame three basic propositions: (1) a non-normative, animistic understanding of geologic subjectivity could trouble accepted criteria for life on earth, leading to kinship with geogenic entities; (2) soil formation (pedogenesis) could be interpreted as a performative process of learning and becoming, rather than simply weathering and aging, with appreciable ontological implications; and (3) soil kinship is situated within a dynamic interplay of resistance and consent, demanding that the terms of reciprocity between humans and soils be mutually beneficial and appropriate to the slowed-down timescale of events in which soil-beings live and operate. The article integrates theoretical provocations with performative scores to expand and sensitize soil-scientific knowledge while, at the same time, contributing to multispecies scholarship on kin-making with geogenic and pedogenic others.
Geopoetics
Authors: Bobbette Adam
Published: December 2023

This article presents an alternative political history of recent planetary thought through an examination of geopoetics rooted in the colonial politics of Indonesia and Cold War geosciences. This history reveals how geopoetics has not been marginal or critical of dominant scientific narratives but has been central to the development of modern theories of the earth. The article traces the roots of that history in colonial Indonesia through debates between geologists, Theosophists, and orientalists, and in colonial endeavors to suppress Javanese Islam through new geological narratives. It considers the work of Johannes Umbgrove, his theory of geopoetry, and its influence on Harry Hess and the theory of plate tectonics. Acknowledging this history shows us just how deeply connected geopoetics is to much longer religious, cosmological, and political conversations about narrating the earth. The article examines how geopoetics has long been preoccupied with understanding the connectivity of nature and catastrophic histories and points to contemporary possibilities for rethinking the relationship between humans, the earth, and cosmos.