bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological Characteristics of Young and Old Murine Hematopoietic Stem Cell Niches, as Modeled In Vitro
Authors: Justin Mojca , Randl Ema Rogač , Kononenko Veno , Hočevar Matej , Drobne Damjana , Rožman Primož
Published: April 2023

The hematopoietic stem cell (HSC) niche undergoes detrimental changes with age. The molecular differences between young and old niches are well studied and understood; however, young and old niches have not yet been extensively characterized in terms of morphology. In the present work, a 2D stromal model of young and old HSC niches isolated from bone marrow was investigated using light and scanning electron microscopy (SEM) to characterize cell density after one, two, or three weeks of culturing, cell shape, and cell surface morphological features. Our work is aimed at identifying morphological differences between young and old niche cells that could be used to discriminate between their respective murine HSC niches. The results show several age-specific morphological characteristics. The old niches differ from the young ones in terms of lower cell proliferating capacity, increased cell size with a flattened appearance, increased number of adipocytes, and the presence of tunneling nanotubes. In addition, proliferating cell clusters are present in the young niches but not in the old niches. Together, these characteristics could be used as a relatively simple and reliable tool to discriminate between young and old murine HSC niches and as a complementary approach to imaging with specific cellular markers.
Using Resin Infiltration Technique and Direct Composite Restorations for the Treatment of Carious Lesions with Different Depths
Authors: Sadıkoğlu İsmail Serhat
Published: April 2023

Minimally invasive treatment methods are of special interest in restorative dental practice, with numerous methods emerging in the last decade. Such methods are being developed to encompass various applications, an important one being the detection and treatment of caries in the early stages. White spot lesions are the earliest visible stage of the caries process. These lesions have a chalky, opaque appearance, which results in esthetic dissatisfaction. In contrast to the principles of minimally invasive dentistry, considerable amounts of sound tooth structure need to be sacrificed to get rid of these lesions. Therefore, caries infiltration has been introduced as an alternative treatment option for non-cavitated lesions. The resin infiltration technique only works in non-cavitated lesions. Replacement of lost dental tissue with resin composites remains the mainstay therapy in cases with cavity formation. This case report describes a case of caries with lesions of varying depths. In such cases, a combination of treatment methods may be used to provide satisfying esthetics with a minimally invasive approach.
The Effect of Lifting‐and‐Thrusting Laser Acupuncture on Electrodermal Activity of Acupoints, Pulse Characteristics, and Brainwave
Authors: Lan Kun-Chan , Lee Chang-Yin , Kuo Kai-Yuan , Wang Chih-Yu
Published: April 2023

Acupuncture has been shown as an effective traditional Chinese medicine treatment method, especially for pain relief. Recently, laser acupuncture is becoming increasingly popular, thanks to its noninvasive and painless nature and effectiveness in treating diseases, proven by many studies (for example, some previous studies showed that low‐power laser stimulation is able to increase the power of alpha rhythms and theta waves). In our prior work, we developed a novel laser acupuncture model that emulates lifting‐and‐thrusting operation commonly used in traditional needle acupuncture and showed its benefit in improving cardiac output and peripheral circulation. By extending our previous studies, in this work, we perform extensive experiments to understand the effect of such a system on electrodermal activity (EDA) of acupoints, pulse characteristics, and brainwave, to further verify its efficacy. In particular, we found that laser stimulation could cause significant changes in EDA of acupoints, pulse amplitude, pulse‐rate‐variability (PRV), and acupoint conductance, as a function of laser power and stimulation time. In addition, laser acupuncture with the lifting‐and‐thrusting operation has more significant effect on increasing the power of alpha and theta frequency bands as compared to laser acupuncture without the lifting‐and‐thrusting operation. Finally, given sufficient stimulation time (e.g., > 20 min), the performance of a low‐powered laser acupuncture with the lifting‐and‐thrusting operation could be comparable to that of traditional needle acupuncture.
The Role of TSLP in Atopic Dermatitis: From Pathogenetic Molecule to Therapeutical Target
Authors: Luo Jialiang , Zhu Zhengyumeng , Zhai Yumeng , Zeng Junxiang , Li Lei , Wang Di , Deng Fan , Chang Bo , Zhou Jia , Sun Ledong
Published: April 2023

Atopic dermatitis (AD) is a kind of chronic skin disease with inflammatory infiltration, characterized by skin barrier dysfunction, immune response dysregulation, and skin dysbiosis. Thymic stromal lymphopoietin (TSLP) acts as a regulator of immune response, positively associated with AD deterioration. Mainly secreted by keratinocytes, TSLP interacts with multiple immune cells (including dendritic cells, T cells, and mast cells), following induction of Th2-oriented immune response during the pathogenesis of AD. This article primarily focuses on the TSLP biological function, the relationship between TSLP and different cell populations, and the AD treatments targeting TSLP.
The Discriminants of Long and Short Duration Failures in Fulfillment Sortation Equipment: A Machine Learning Approach
Authors: Mutemi Abed , Bacao Fernando
Published: April 2023

Due to the difficulties inherent in diagnostics and prognostics, maintaining machine health remains a substantial issue in industrial production. Current approaches rely substantially on human engagement, making them costly and unsustainable, especially in high-volume industrial complexes like fulfillment centers. The length of time that fulfillment center equipment failures last is particularly important because it affects operational costs dramatically. A machine learning approach for identifying long and short equipment failures is presented using historical equipment failure and fault data. Under a variety of hyperparameter configurations, we test and compare the outcomes of eight different machine learning classification algorithms, seven individual classifiers, and a stacked ensemble. The gradient boosting classifier (GBC) produces state-of-the-art results in this setting, with precision of 0.76, recall of 0.82, and false positive rate (FPR) of 0.002. This model has since been applied successfully to automate the detection of long- and short-term defects, which has improved equipment maintenance schedules and personnel allocation towards fulfillment operations. Since its launch, this system has contributed to saving over $500 million in fulfillment expenses. It has also resulted in a better understanding of the flaws that cause long-term failures, which is now being used to build more sophisticated failure prediction and risk-mitigation systems for fulfillment equipment.
Antidepressant and Anxiolytic Potentials of the Chewing Stick, Salvadora persica
Authors: Vasudevan Rajalakshimi , Kandasamy Geetha , Aldahish Afaf , Almanasef Mona , Khobrani Moteb , Shorog Eman , Prabahar Kousalya , Mohammed Alsawaq Enas , Wahab Shadma , Begum M. Yasmin , Paulsamy Premalatha
Published: April 2023

Purpose and Objectives. The quest for psychoactive plants possessing therapeutic potential has evolved emerging interest. Salvadora persica (Sp), belonging to the Salvadoraceae family, known as miswak, is a medicinal plant; most of its published research is on oral health, with promising antimicrobial, anti-inflammatory, and antiproliferative activity. However, given its widespread use, only few studies are associated with its potential neuropharmacological effect. Therefore, this study aims to assess the possible anxiolytic and antidepressant effects of Salvadora persica using animal models. Materials and Methods. Salvadora persica stem bark was extracted with two different solvents, i.e., ethyl acetate and water, and preliminary phytochemical screening was performed. Two behavioral models were used: an elevated plus maze test (EPM) and the light and dark model test for anxiolytic parameters, and a forced swim test (FST) for antidepressant effects. Healthy mice weighing 18−40 gms were treated orally in four groups (n = 6), i.e., negative control treated with normal saline and positive control with 1 mg/kg diazepam (EPM) and 30 mg/kg fluoxetine (FST), and the test groups were treated with 500 mg/kg of aqueous and ethyl acetate Sp extract. The number of entries and duration spent in the open arm for 5 minutes were the parameters for evaluating the anxiolytic activity (EPM). Duration of immobility was measured for 5 min in the FST model. Results. In EPM, both the Sp extracts significantly (p < 0.005) increased the number of entries and the time spent in the open arms and was much similar to those of diazepam. Similarly, these extracts and fluoxetine significantly (p < 0.005) decreased the immobility time in FST. Conclusion. The results suggest the therapeutic potential of Salvadora persica an alternative in the management of comorbid anxiety and depression.
Covers and Envelopes by Submodules or Quotient-Modules
Authors: Zeng Yuedi
Published: April 2023

Let

R

be a ring,

X

a class of left

R

-modules,

S

the class of submodules of

X

, and

Q

the class of quotient-modules of

X

. It is shown that

S

Q

is precovering (preenveloping) if and only if every injective (projective) left

R

-module has an

X

-precover (

X

-preenvelope). Both epic and monic

S

-(pre) covers (

Q

-(pre) envelopes) are studied. Moreover, some applications are given. In particular, it is proven that the injective envelope of any projective left

R

-module is projective if and only if the class of quotient-modules of projective and injective left

R

-modules is monic preenveloping.
Study of the Hydration Mechanism of Portland Cement with Raman Spectroscopy Applying CO2 Laser Radiation
Authors: Quiroz-Portillo D. , Rosales-Candelas I. , Soto-Bernal J. J. , González-Mota R. , Vázquez G. V.
Published: April 2023

This work presents the results by irradiating fresh Portland cement pastes with CO2 laser, at powers of 1.6, 2.0, and 2.4 W, at different water-to-cement (w/c) ratios 0.4, 0.45, and 0.5. Raman spectra show the evolution and accelerated growth of the main hydration products through the intensity changes of the Raman signal. The Raman shifts reveal that the C-S-H, CH, AFt, and CaCO3 bands are detected in a shorter time, which means that the setting times are also reduced. The detected band of calcium carbonate, which is due to the incorporation of limestone during the grinding process, shows that it is responsible largely for the acceleration in the reactions during the hydration of the cement. The Raman signals of the hydration products of nonirradiated cement pastes present a delay in their evolution with respect to the irradiated pastes. The curves obtained from the Raman spectra can be used to model the mechanism of hydration as well as to understand the setting process.
Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications
Authors: Gouda Mohamed A. , Nelson Blessie E. , Buschhorn Lars , Wahida Adam , Subbiah Vivek
Published: April 2023

Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation
Authors: Sivakumar Smruthy , Moore Jay A. , Montesion Meagan , Sharaf Radwa , Lin Douglas I. , Colón Caterina I. , Fleishmann Zoe , Ebot Ericka M. , Newberg Justin Y. , Mills Jennifer M. , Hegde Priti S. , Pan Quintin , Dowlati Afshin , Frampton Garrett M. , Sage Julien , Lovly Christine M.
Published: April 2023

Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that were human papillomavirus–positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival, whereas CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer.

Significance:

Minimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes and novel recurrent mutations as well as an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC.

This article is highlighted in the In This Issue feature, p. 1501
A Transcriptome-Based Precision Oncology Platform for Patient–Therapy Alignment in a Diverse Set of Treatment-Resistant Malignancies
Authors: Mundi Prabhjot S. , Dela Cruz Filemon S. , Grunn Adina , Diolaiti Daniel , Mauguen Audrey , Rainey Allison R. , Guillan Kristina , Siddiquee Armaan , You Daoqi , Realubit Ronald , Karan Charles , Ortiz Michael V. , Douglass Eugene F. , Accordino Melissa , Mistretta Suzanne , Brogan Frances , Bruce Jeffrey N. , Caescu Cristina I. , Carvajal Richard D. , Crew Katherine D. , Decastro Guarionex , Heaney Mark , Henick Brian S. , Hershman Dawn L. , Hou June Y. , Iwamoto Fabio M. , Jurcic Joseph G. , Kiran Ravi P. , Kluger Michael D. , Kreisl Teri , Lamanna Nicole , Lassman Andrew B. , Lim Emerson A. , Manji Gulam A. , McKhann Guy M. , McKiernan James M. , Neugut Alfred I. , Olive Kenneth P. , Rosenblat Todd , Schwartz Gary K. , Shu Catherine A. , Sisti Michael B. , Tergas Ana , Vattakalam Reena M. , Welch Mary , Wenske Sven , Wright Jason D. , Canoll Peter , Hibshoosh Hanina , Kalinsky Kevin , Aburi Mahalaxmi , Sims Peter A. , Alvarez Mariano J. , Kung Andrew L. , Califano Andrea
Published: April 2023

Predicting in vivo response to antineoplastics remains an elusive challenge. We performed a first-of-kind evaluation of two transcriptome-based precision cancer medicine methodologies to predict tumor sensitivity to a comprehensive repertoire of clinically relevant oncology drugs, whose mechanism of action we experimentally assessed in cognate cell lines. We enrolled patients with histologically distinct, poor-prognosis malignancies who had progressed on multiple therapies, and developed low-passage, patient-derived xenograft models that were used to validate 35 patient-specific drug predictions. Both OncoTarget, which identifies high-affinity inhibitors of individual master regulator (MR) proteins, and OncoTreat, which identifies drugs that invert the transcriptional activity of hyperconnected MR modules, produced highly significant 30-day disease control rates (68% and 91%, respectively). Moreover, of 18 OncoTreat-predicted drugs, 15 induced the predicted MR-module activity inversion in vivo. Predicted drugs significantly outperformed antineoplastic drugs selected as unpredicted controls, suggesting these methods may substantively complement existing precision cancer medicine approaches, as also illustrated by a case study.

Significance:

Complementary precision cancer medicine paradigms are needed to broaden the clinical benefit realized through genetic profiling and immunotherapy. In this first-in-class application, we introduce two transcriptome-based tumor-agnostic systems biology tools to predict drug response in vivo. OncoTarget and OncoTreat are scalable for the design of basket and umbrella clinical trials.

This article is highlighted in the In This Issue feature, p. 1275
Supplementary Figures from High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects
Authors: Kawase Katsushige , Kawashima Shusuke , Nagasaki Joji , Inozume Takashi , Tanji Etsuko , Kawazu Masahito , Hanazawa Toyoyuki , Togashi Yosuke
Published: April 2023

Supplementary Figure S1-S7
Data from High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects
Authors: Kawase Katsushige , Kawashima Shusuke , Nagasaki Joji , Inozume Takashi , Tanji Etsuko , Kawazu Masahito , Hanazawa Toyoyuki , Togashi Yosuke
Published: April 2023

Abstract
IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB–targeted therapies to overcome such resistance.

See related Spotlight by Haugh and Daud, p. 864
Data from High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects
Authors: Kawase Katsushige , Kawashima Shusuke , Nagasaki Joji , Inozume Takashi , Tanji Etsuko , Kawazu Masahito , Hanazawa Toyoyuki , Togashi Yosuke
Published: April 2023

Abstract
IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB–targeted therapies to overcome such resistance.
High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects
Authors: Kawase Katsushige , Kawashima Shusuke , Nagasaki Joji , Inozume Takashi , Tanji Etsuko , Kawazu Masahito , Hanazawa Toyoyuki , Togashi Yosuke
Published: April 2023

IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB–targeted therapies to overcome such resistance.

See related Spotlight by Haugh and Daud, p. 864
Razão calcinada: crítica de teatro Amazonas, da companhia Azkona & Toloza
Authors: Santos Valmir Jesus dos
Published: April 2023

Espetáculo denuncia a promíscua e histórica cumplicidade de governos e da iniciativa privada com atividades extrativistas ilícitas, motores da crise ambiental na Amazônia, bioma que tem 60% de sua extensão no norte do Brasil. Chama a atenção por meio de procedimentos do documentário audiovisual, da técnica verbatim e das formas animadas que ganham dimensões sensoriais. Há uma lógica intrínseca em termos de dramaturgia expandida, como na confluência de volumes, luzes, sombras e objetos que pouco a pouco transformam o palco nu em uma instalação escultórica.
Projected Changes to Streamflow and Stream Temperature in Central Texas: How Much Will the River Flow?
Authors: Wootten Adrienne M. , Martin Elinor , Randklev Charles R. , Smith Ryan
Published: April 2023

Riverine ecosystems are dependent in large part on the climate of the region, and climate change is expected to alter climatic factors of interest, such as precipitation, temperature, and evapotranspiration. In central Texas, precipitation is expected to decrease while temperature increases as the climate changes. Drought and flooding events are also expected to increase in the region, which will also affect streamflow and stream temperature in riverine ecosystems. Numerous studies have assessed the potential impacts of climate change on riverine species. This study examines the projected climate changes, determines potential changes in streamflow and stream temperature for river basins in central Texas, and assesses the appropriate uses of climate projections for riverine species impact assessments, using the Texas fatmucket (Lampsilis bracteata) as a case study. Previously established regression methods were used to produce projections of streamflow and stream temperature. This study finds that streamflow is projected to decrease and stream temperature is projected to increase. Using thermal tolerance thresholds previously determined for the Lampsilis bracteata, this study also finds that the lethal temperature events for the Lampsilis bracteata will increase. This study makes several recommendations on the use of downscaled climate projections for impact assessments for riverine species such as the Lampsilis bracteata.
RPL21 interacts with LAMP3 to promote colorectal cancer invasion and metastasis by regulating focal adhesion formation
Authors: Zhu Jiaxian , Long Ting , Gao Lingfang , Zhong Yan , Wang Ping , Wang Xiaoyan , Li Zuguo , Hu Zhiyan
Published: April 2023

Background

Metastasis is the leading cause of death among patients with colorectal cancer (CRC). Therefore, it is important to explore the molecular mechanisms of metastasis to develop effective therapeutic targets for CRC. In the present study, ribosomal protein L21 (RPL21) was considered as being involved in promoting CRC metastasis, yet the underlying mechanism requires further investigation.

Methods

Immunohistochemistry, western blotting, and quantitative reverse transcription polymerase chain reaction were performed to measure the expression of RPL21 and lysosome-associated membrane protein 3 (LAMP3) in CRC tissues and cells. Wound healing, transwell migration, and invasion assays were performed to study the migration and invasion of cultured CRC cells. An orthotopic CRC mouse model was developed to investigate the metastatic ability of CRC. Transcriptome sequencing was conducted to identify the genes related to RPL21. The dual-luciferase reporter gene assay was performed to determine the transcriptional activity of transcription factor EB (TFEB). The GST/His pull-down assay was performed to investigate the specific binding sites of RPL21 and LAMP3. The cell adhesion assay was performed to determine the adhesion ability of CRC cells. Immunofluorescence staining was performed to observe focal adhesions (FAs).

Results

RPL21 was highly expressed in CRC, contributing to tumor invasiveness and poor patient prognosis. Functionally, RPL21 promoted the migration and invasion of CRC cells in vitro and tumor metastasis in vivo. Moreover, LAMP3 was identified as being highly related to RPL21 and was essential in promoting the migration and invasion of CRC cells. Mechanistically, RPL21 activated the transcriptional function of TFEB to upregulate LAMP3 expression. RPL21 directly bound to the aa 341–416 domain of LAMP3 via its aa 1–40 and aa 111–160 segments. The combination of RPL21 and LAMP3 enhanced the stability of the RPL21 protein by suppressing the degradation of the ubiquitin–proteasome system. Furthermore, RPL21 and LAMP3 promoted the formation of immature FAs by activating the FAK/paxillin/ERK signaling pathway.

Conclusions

RPL21 promoted invasion and metastasis by regulating FA formation in a LAMP3-dependent manner during CRC progression. The interaction between RPL21 and LAMP3 may function as a potential therapeutic target against CRC.
Powering Ghana’s future: unraveling the dynamics of electricity generation and the path to sustainable energy
Authors: Atuahene Sampson Agyapong , Sheng Qian Xu
Published: April 2023

This study investigates powering Ghana’s future: unraveling the dynamics of electricity generation and the path to sustainable energy by estimating endogenous parameters and employing an unrestricted Vector Autoregression (VAR) model. The model examines the linear lead–lag relationships between variables in the Ghanaian electricity sector and power consumption, using data from 2002 to 2021. The results reveal structural long-and-short-run headwinds for the unrestricted models and indicate that the growth rate of the Gross Domestic Product (GDP) and electricity from fossil fuels are directly correlated. Granger causality analysis highlights a feedback relationship between GDP growth rate and electricity from fossil fuel sources. The impulse response function reveals that the GDP growth rate is sensitive to exogenous shocks with lasting effects. Variance decomposition results show that renewable energy without hydropower explains a minimal variance due to shocks, while total global greenhouse emissions account for a significant proportion of the variance due to headwinds. Electricity from fossil fuel sources explains a substantial part of the variance due to headwinds, suggesting Ghana’s overreliance on conventional energy sources. The study forecasts that installed renewable energy capacity will experience considerable growth by 2036, accounting for most of the energy mix. To promote a sustainable energy future, the study recommends implementing fiscal instruments that incentivize renewable energy consumption, gradually diversifying the energy mix towards natural gas as a medium-term transition fuel for grid electricity generation and shifting entirely to renewables in the long time. This research contributes valuable insights into the dynamics of electricity generation in Ghana and provides policy recommendations for sustainable energy development.
PCK1 activates oncogenic autophagy via down-regulation Serine phosphorylation of UBAP2L and antagonizes colorectal cancer growth
Authors: Zhang Xiangyan , Tao Geru , Jiang Jie , Qu Tingting , Zhao Shuchao , Xu Ping , Zhao Ya’nan , Xing Xiaoming , Qin Shucun
Published: April 2023

Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme in gluconeogenesis. PCK1 is considered an anti-oncogene in several human cancers. In this study, we aimed to determine the functions of PCK1 in colorectal cancer (CRC). PCK1 expression in CRC tissues was tested by western blot and immunohistochemistry analyses and associations of PCK1 level with clinicopathological characteristics and disease survival evaluated. Further, we studied the effect of PCK1 on CRC cell proliferation and the underlying mechanisms. Our results show that PCK1 is expressed at significantly lower levels in CRC than in control tissues. High PCK1 expression was correlated with smaller tumor diameter and less bowel wall invasion (T stage). Overexpression and knockdown experiments demonstrated that PCK1 inhibits CRC cell growth both in vitro and in vivo. Mechanistically, PCK1 antagonizes CRC growth via inactivating UBAP2L phosphorylation at serine 454 and enhancing autophagy. Overall, our findings reveal a novel molecular mechanism involving PCK1 and autophagy, and highlight PCK1 as a promising candidate therapeutic target in CRC.
CAFs-derived rho-associated kinase1 mediated EMT to promote laryngeal squamous cell carcinoma metastasis
Authors: Yang Liyun , Gong Shiqi , Qiao Peipei , Zhao Runyu , Huang Shuixian , Zhou Jieyu , Hu An
Published: April 2023

Background

Cancer-associated fibroblasts (CAFs) play an essential role in tumorigenesis and development of cancers. Nevertheless, the specific molecular mechanism of tumorigenesis and development in Laryngeal squamous cell carcinoma (LSCC) still unknown.

Methods

CAFs, CPFs and NFs were isolated and identified from laryngeal cancer, para-laryngeal cancer and normal tissues. Immunofluorescent staining, Rt-PCR and Western Blot were used to detect the expression of related proteins. Wound healing, migration, invasion and animal experiments were used to examine the ability of movement, migration, invasion and metastasis of LSCC.

Results

ROCK1, was highly expressed in CAFs and CAFs enhanced LSCC metastasis in vivo and vitro, and downregulation of ROCK1 in CAFs inhibited the migration and invasion of LSCC cells. While increasing ROCK1 expression in NFs promoted the migration and invasion of LSCC cells. Further studies revealed that epithelial-mesenchymal transition (EMT) and JAK2/STAT3/ERK1/2 pathway might play an essential role in promoting metastasis of LSCC. In addition, inhibition activity of ROCK1 or JAK2/STAT3/ERK1/2 signal molecules significantly reduced EMT and metastasis.

Conclusions

CAFs-derived ROCK1 via JAK2/STAT3/ERK1/2 axis mediated EMT to promote LSCC metastasis and targeting ROCK1 might provide a potential treatment strategy for LSCC.
Identification of mitochondrial respiratory chain signature for predicting prognosis and immunotherapy response in stomach adenocarcinoma
Authors: Yang Jing , Jin Feifan , Li Huanjuan , Shen Yuhuan , Shi Weilin , Wang Lina , Zhong Lei , Wu Gongqiang , Wu Qiaoliang , Li Yanchun
Published: April 2023

Stomach adenocarcinoma (STAD) is the third leading cause of cancer-related deaths and the fifth most prevalent malignancy worldwide. Mitochondrial respiratory chain complexes play a crucial role in STAD pathogenesis. However, how mitochondrial respiratory chain complex genes (MRCCGs) affect the prognosis and tumor microenvironment in STAD remains unclear. In this study, we systematically analyzed genetic alterations and copy number variations of different expression densities of MRCCGs, based on 806 samples from two independent STAD cohorts. Then we employed the unsupervised clustering method to classify the samples into three expression patterns based on the prognostic MRCCG expressions, and found that they were involved in different biological pathways and correlated with the clinicopathological characteristics, immune cell infiltration, and prognosis of STAD. Subsequently, we conducted a univariate Cox regression analysis to identify the prognostic value of 1175 subtype-related differentially expressed genes (DEGs) and screened out 555 prognostic-related genes. Principal component analysis was performed and developed the MG score system to quantify MRCCG patterns of STAD. The prognostic significance of MG Score was validated in three cohorts. The low MG score group, characterized by increased microsatellite instability-high (MSI-H), tumor mutation burden (TMB), PD-L1 expression, had a better prognosis. Interestingly, we demonstrated MRCCG patterns score could predict the sensitivity to ferroptosis inducing therapy. Our comprehensive analysis of MRCCGs in STAD demonstrated their potential roles in the tumor-immune-stromal microenvironment, clinicopathological features, and prognosis. Our findings highlight that MRCCGs may provide a new understanding of immunotherapy strategies for gastric cancer and provide a new perspective on the development of personalized immune therapeutic strategies for patients with STAD.
SIAH1 ubiquitination-modified HMGCR inhibits lung cancer progression and promotes drug sensitivity through cholesterol synthesis
Authors: Yuan Hongmei , Wu Hongge , Cheng Jing , Xiong Jie
Published: April 2023

Backgrounds

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide. Deep understanding of chemoresistance will lead to remarkable progress in lung cancer treatment strategy. Cholesterol accumulation was associated with cisplatin resistance in lung cancer treatment. And we found the degree of cisplatin resistance was correlated with the expression of the cholesterol synthesis HMGCR.

Methods

We analyzed a group of 42 lung cancer patients who received cisplatin treatment after lung resection surgery. The expression of HMGCR and its correlation with cholesterol in lung cancer cell lines were determined by qRT-PCR and ELISA analyses. We focus on the function and mechanism of HMGCR in lung cancer and reveal that knockdown of HMGCR expression inhibits the proliferation, colony formation, and migration of lung cancer cell lines in vitro or in vivo and dramatically enhances the efficacy of cisplatin.

Results

Through mechanism studies, we illustrate that SIAH1, an E3 ubiquitin-protein ligase, ubiquitination modifies HMGCR and inhibits efflux protein activity via regulating cholesterol synthesis. In vivo experiments showed that SIAH1 overexpression or using HMGCR knockdown retard tumor growth and enhanced the efficacy of cisplatin. In summary, HMGCR affects cholesterol metabolism by regulating key enzymes in cholesterol synthesis, thereby reducing drug sensitivity.

Conclusion

This study indicates that lung cancer patients with lower HMGCR levels may lead to a better prognosis and provide a potential treatment by SIAH1 overexpression for lung cancer patients with cisplatin resistance.
Antioxidants-related nuclear factor erythroid 2-related factor 2 gene variants associated with HBV-related liver disease
Authors: Liu Yanqiong , Wu Qiulian , Zhang Fuyong , Qin Xue
Published: April 2023

Background

Accumulating evidence demonstrated that nuclear factor erythroid 2-related factor 2 (NRF2) expression plays a crucial role in the proliferation, invasion and metastasis of hepatocellular carcinoma (HCC). However, research on the effect of NRF2 genetic polymorphism on the development of chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC) and HCC is still missing.

Methods

A total of 673 individuals were included in the study and classified into four groups: 110 CHB cases, 86 LC cases, 260 HCC cases, and 217 healthy controls. ​The polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method were used to detect rs6721961 and rs6726395 polymorphisms.

Results

Patients carrying the T allele in rs6721961 were at a higher risk of HCC than individuals with the G allele compared to CHB patients (OR = 1.561, 95%CI: 1.003–2.430, P = 0.048). The statistically significant differences were also found in the rs6721961 GT genotype (OR = 2.298, 95% CI: 1.282–4.119, P = 0.005) and dominant model (OR = 2.039, 95% CI: 1.184–0.510, P = 0.010). Subgroup analysis also detected a significant association between the rs6721961 T allele and the development of HCC in older subjects (≥ 50 years) (OR = 2.148, 95% CI: 1.208–3.818, P = 0.009). Statistical analysis results indicated that subjects carrying haplotype G-A had a lower risk of HCC (OR = 0.700, 95% CI: 0.508–0.965, P = 0.028).

Conclusions

For the first time, our findings provide evidence that the NRF2 gene rs6721961 variation is a potential genetic marker of susceptibility to HCC.
Utilization of mental health services in relation to the intention to reduce chemsex behavior among clients from an integrated sexual health services center in Taiwan
Authors: Hung Yu-Ru , Chuang Tsan-Tse , Chen Tsai-Wei , Chung An-Chun , Wu Meng-Tzu , Hsu Su-Ting , Ko Nai-Ying , Strong Carol
Published: April 2023

Introduction

The intention of chemsex-practicing gay and bisexual men and other men who have sex with men (GBMSM) to reduce their drug use is an important factor for the utilization of harm reduction services. This study aimed to examine data from an integrated sexual health services center to understand the relationship between the intention to reduce chemsex behavior and chemsex-related utilization of mental health services among GBMSM who engage in chemsex.

Method

We used data collected from Healing, Empowerment, Recovery of Chemsex (HERO), an integrated health center in Taiwan, between November 2017 and December 2021. As the baseline, clients were asked to rate the current and ideal proportions of their sexual activities that involved the use of MDMA, ketamine, methamphetamine, GHB/GBL, or mephedrone. Having the intention to reduce chemsex was defined as having a lower proportion of ideal engagement compared to actual engagement. The data on the use of the services provided at HERO were linked to the survey responses and compared to information gathered during regular follow-up visits. Univariable and multivariable logistic regression analyses and a Poisson regression analysis were performed on the data.

Results

A total of 152 GBMSM reported engaging in chemsex, of whom 105 (69.1%) expressed the intention to reduce their chemsex behavior. Service utilization ranged from 23.0% for participating in meetings of a chemsex recovery group, 17.1% for visiting a mental health clinic, and 10.5% for using both of these services. The intention to reduce chemsex behavior significantly associated with visiting a mental health clinic (aOR = 4.68, p < 0.05), but its association with attending meetings of a chemsex recovery group was only marginally significant (aOR = 2.96, p < 0.1). Other factors that remained significantly associated with service use were a high frequency of substance use and living with HIV.

Conclusion

Comprehensive harm reduction strategies, which touch on mental health, drug use management and recovery, are needed for those who want to reduce their chemsex behavior. Public health practitioners should endeavor to raise awareness of resources that are available for people who engage in chemsex and to minimize the barriers blocking their access to the appropriate services.
Brevilin A is a potent anti-metastatic CRC agent that targets the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay
Authors: Fan Xueying , Meng Mingjing , Li Baoting , Chen Hui , Tan Jincheng , Xu Keyang , Xiao Shilin , Kwan Hiu-Yee , Liu Zhongqiu , Su Tao
Published: April 2023

Background

More than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC).

Methods

Conditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis.

Results

In the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo.

Conclusions

We are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.
The interplay between androgens and the immune response in polycystic ovary syndrome
Authors: Shabbir Sania , Khurram Emaan , Moorthi Vedhika Sathya , Eissa Youssef Tamer Hassan , Kamal Mohammad Azhar , Butler Alexandra E.
Published: April 2023

Polycystic ovary syndrome (PCOS) is a metabolic-reproductive-endocrine disorder that, while having a genetic component, is known to have a complex multifactorial etiology. As PCOS is a diagnosis of exclusion, standardized criteria have been developed for its diagnosis. The general consensus is that hyperandrogenism is the primary feature of PCOS and is associated with an array of physiological dysfunctions; excess androgens, for example, have been correlated with cytokine hypersecretion, adipocyte proliferation, and signaling pathway dysregulation. Another key feature of PCOS is insulin resistance, resulting in aberrant glucose and fatty acid metabolism. Additionally, the immune system plays a key role in PCOS. Hyperandrogenism stimulates some immune cells while it inhibits others, thereby disrupting the normal balance of immune cells and creating a state of chronic inflammation. This low-grade inflammation could contribute to infertility since it induces ovarian dysfunction. This dysregulated immune response in PCOS exhibits autoimmunity characteristics that require further investigation. This review paper examines the relationship between androgens and the immune response and how their malfunction contributes to PCOS.
Camrelizumab for cancers in patients living with HIV: one-single center experience
Authors: Wu Menghua , Zheng Xin , Zhang Yu , Song Jian , Zhao Jimao
Published: April 2023

Objectives

The primary objective was to evaluate the safety of the anti-PD-1 antibody camrelizumab in people living with HIV (PLWH); the secondary objective was to evaluate tumor response.

Methods

From May 8, 2018, to December 10, 2021, twenty-four patients with HIV and advanced cancer as well as a CD4+ T-cell count greater than or equal to 100 cells/µL were treated with camrelizumab in daily practice. We describe the demographic characteristics, safety, and clinical course of these 24 PLWH with cancer treated with camrelizumab. Safety was assessed using the current Common Terminology Criteria for Adverse Events (CTCAE). The tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).

Results

The median number of cycles was 8 (4–26). Only two grade 3 adverse reactions were reported (no toxic deaths or immune-related deaths). Among the 24 patients, 2 (8%) complete responses and 6 (25%) partial responses were observed. 7 patients (29%) were at stable tumor status and others progressed.

Conclusions

Data from the present study strongly support the use of camrelizumab (monoclonal antibodies targeting the PD-1 pathway) in this population, as it appears to be a feasible approach with no deleterious effects on PLWH and tolerability and acceptable efficacy. In addition, these findings further support the inclusion of PLWH with cancer in clinical trials evaluating the safety and efficacy of ICIs on cancer.