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Journal of Translational Medicine Apr 2024Cancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major... (Review)
Review
Cancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major complication of many advanced cancers and seriously affects the quality of life and survival of cancer patients. However, the specific molecules that mediate cancer-related cachexia remain elusive, and the fundamental cellular and molecular mechanisms associated with muscle atrophy and lipidolysis in cancer patients still need to be investigated. Exosomes, a newly discovered class of small extracellular vesicles that facilitate intercellular communication, have a significant role in the onset and development of various cancers. Studies have shown that exosomes play a role in the onset and progression of cancer-related cachexia by transporting active molecules such as nucleic acids and proteins. This review aimed to provide an overview of exosome developments in cancer-induced skeletal muscle atrophy and adipose tissue degradation. More importantly, exosomes were shown to have potential as diagnostic markers or therapeutic strategies for cachexia and were prospected, providing novel strategies for the diagnosis and treatment of cancer-related cachexia.
Topics: Cachexia; Humans; Exosomes; Neoplasms; Animals; Adipose Tissue; Muscular Atrophy
PubMed: 38689293
DOI: 10.1186/s12967-024-05201-y -
Clinical Cancer Research : An Official... Nov 2023Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide...
PURPOSE
Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo.
EXPERIMENTAL DESIGN
Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo.
RESULTS
Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule.
CONCLUSIONS
RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.
Topics: Humans; NAD; Cytokines; Nicotinamide Phosphoribosyltransferase; Pyrazoles; Necrosis; Rhabdomyosarcoma; Cell Line, Tumor
PubMed: 37616468
DOI: 10.1158/1078-0432.CCR-23-0200 -
Histology and Histopathology Dec 2023Fibroblast specific protein 1 (FSP1)/S100A4 is a calcium binding protein which has been linked to epithelial-mesenchymal transition, tissue fibrosis, pulmonary vascular...
Fibroblast specific protein 1 (FSP1)/S100A4 is a calcium binding protein which has been linked to epithelial-mesenchymal transition, tissue fibrosis, pulmonary vascular disease, metastatic tumour development, increased tumour cell motility and invasiveness. This protein is reported to be also expressed in newly formed and differentiated fibroblasts and has been used in various studies to demonstrate epithelial-mesenchymal transition (EMT). We aimed to characterize S100A4 positive cells in different human tissue compartments, with the focus on fibroblasts/myofibroblast. We found S100A4 expression in a wide range of cells. Fibroblasts/myofibroblasts showed a broad spectrum of staining intensity, ranging from negative to strong expression of S100A4, with the strongest expression in smooth muscle actin positive myofibroblasts. Cells of haematopoietic lineage, namely CD4 and CD8 positive T-lymphocytes, but not B-lymphocytes expressed S100A4. All investigated monocytes, macrophages and specialised histiocytes were positive for S100A4. Even some epithelial cells of the kidney and bladder were positive for S100A4. Expression was also found in the vasculature. Here, cells of the subendothelial space, tunica adventitia and some smooth muscle cells of the tunica media were positive for S100A4. In summary, S100A4 is expressed in various cell types of different lineage and is not, as originally believed, specific for fibroblasts (FSP). Results attained under the premise of specificity of FSP1/S100A4 for fibroblasts, like the founding research on EMT type 2 in kidney and liver, therefore need to be reinterpreted.
Topics: Humans; S100 Calcium-Binding Protein A4; Kidney; Calcium-Binding Proteins; Fibrosis; Fibroblasts; Neoplasms
PubMed: 37154201
DOI: 10.14670/HH-18-621 -
BMC Women's Health Aug 2023Hysteroscopic surgery and assisted reproduction technology are feasible ways to improve the reproductive outcome. Our aim was to study hysteroscopic septoplasty and...
INTRODUCTION
Hysteroscopic surgery and assisted reproduction technology are feasible ways to improve the reproductive outcome. Our aim was to study hysteroscopic septoplasty and myomectomy's effect on infertility and reproductive performance.
METHODS
Retrospective cohort of patients who had unexplained infertility and/or recurrent miscarriages and had myomectomy or septoplasty in the period September 2016-october 2021 with a total of 18 months' follow up. The main outcome measures were spontaneous pregnancy, term pregnancy and miscarriage. For analysis, we used Statistical Package for Social Sciences (SPSS) version 20.
RESULTS
One hundred and sixty-five patients were included. The mean age of patients was 39 years. 40 patients had septum resection and 125 patients had hysteroscopic myomectomy. A spontaneous pregnancy rate after surgery was achieved in 46 patients (27.9%). Out of the 64 patients who had failed IVF preoperatively, 32 patients (50%) had a successful IVF post-hysteroscopic surgery and there were more successful cases in the patients who had fibroid resection but this difference did not reach a statistical significance (P value 0.055). In the 79 pregnancies after surgery, preterm birth and miscarriage were seen in 10 patients (12.7%), similarly, respectively after septal or fibroid resection. Miscarriages were less post-operatively. Hysteroscopic myomectomy, compared with hysteroscopic metroplasty, was significantly associated with higher spontaneous pregnancy rate (63.0% Vs 37.0%, P value 0.018), more term pregnancies (87.5% vs. 12.5%, P value 0.001) and less miscarriage rate (40%vs 60%, P value 0.003). Pregnancy post-operatively in patients with primary infertility was more statistically significantly associated with hysteroscopic myomectomy than with hysteroscopic septoplasty (95.8% vs. 4.2%, p value 0.030). In patients who got pregnant postoperatively there was no statistically significant difference in the mode of delivery.
CONCLUSION
In carefully selected patients with unexplained infertility and recurrent miscarriage, hysteroscopic myomectomy, compared with hysteroscopic metroplasty, was significantly associated with higher spontaneous pregnancy, more term pregnancies and less miscarriage rates. More than metroplasty, hysteroscopic myomectomy led to higher spontaneous pregnancies in patients with primary infertility.
TRIAL REGISTRATION
NCT05560295.
Topics: Adult; Female; Humans; Infant, Newborn; Pregnancy; Abortion, Habitual; Fertility; Hysteroscopy; Infertility; Leiomyoma; Premature Birth; Reproduction; Retrospective Studies; Uterine Myomectomy
PubMed: 37644542
DOI: 10.1186/s12905-023-02562-2 -
Journal of Cachexia, Sarcopenia and... Oct 2023Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent... (Review)
Review
Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent meta-analyses have reported high heterogeneity in this literature, representing uncertainty in the resulting estimates. Using the setting of palliative-intent chemotherapy as an exemplar, we aimed to systematically summarize the sources of variability among studies evaluating SM and AT change during cancer treatment and propose standards for future studies to enable reliable meta-analysis. Studies that measured computed tomography-defined SM and/or AT change in adult patients during palliative-intent chemotherapy for solid tumours were included, with no date or geographical limiters. Of 2496 publications screened by abstract/title, 83 were reviewed in full text and 38 included for extraction, representing 34 unique cohorts across 8 tumour sites. The timing of baseline measurement was frequently defined as prior to treatment, while endpoint timing ranged from 6 weeks after treatment start to time of progression. Fewer than 50% specified the actual time interval between measurements. Measurement error was infrequently discussed (8/34). A single metric (cm /m , cm or %) was used to describe SM change in 18/34 cohorts, while multiple metrics were presented for 10/34 and no descriptive metrics for 6/34. AT change metrics and sex-specific reporting were available for 10/34 cohorts. Associations between SM loss and overall survival were evaluated in 24 publications, with classification of SM loss ranging from any loss to >14% loss over variable time intervals. Age and sex were the most common covariates, with disease response in 50% of models. Despite a wealth of data and effort, heterogeneity in study design, reporting and statistical analysis hinders evidence synthesis regarding the severity and outcomes of SM and AT change during cancer treatment. Proposed standards for study design include selection of homogenous cohorts, clear definition of baseline/endpoint timing and attention to measurement error. Standard reporting should include baseline SM and AT by sex, actual scan interval, SM and AT change using multiple metrics and visualization of the range of change observed. Reporting by sex would advance understanding of sexual dimorphism in SM and AT change. Evaluating the impact of tissue change on outcomes requires adjustment for relevant covariates and concurrent disease response. Adoption of these standards by researchers and publishers would alter the current paradigm to enable meta-analysis of future studies and move the field towards meaningful application of SM and AT change to clinical care.
Topics: Adult; Female; Humans; Male; Adipose Tissue; Muscle, Skeletal; Neoplasms; Obesity; Reference Standards; Tomography, X-Ray Computed; Meta-Analysis as Topic
PubMed: 37675809
DOI: 10.1002/jcsm.13318 -
Autonomic Neuroscience : Basic &... Feb 2024Cancer cachexia, characterized by muscle wasting and widespread inflammation, poses a significant challenge for patients with cancer, profoundly impacting both their... (Review)
Review
Cancer cachexia, characterized by muscle wasting and widespread inflammation, poses a significant challenge for patients with cancer, profoundly impacting both their quality of life and treatment management. However, existing treatment modalities remain very limited, accentuating the necessity for innovative therapeutic interventions. Many recent studies demonstrated that changes in autonomic balance is a key driver of cancer cachexia. This review consolidates research findings from investigations into autonomic dysfunction across cancer cachexia, spanning animal models and patient cohorts. Moreover, we explore therapeutic strategies involving adrenergic receptor modulation through receptor blockers and agonists. Mechanisms underlying adrenergic hyperactivity in cardiac and adipose tissues, influencing tissue remodeling, are also examined. Looking ahead, we present a perspective for future research that delves into autonomic dysregulation in cancer cachexia. This comprehensive review highlights the urgency of advancing research to unveil innovative avenues for combatting cancer cachexia and improving patient well-being.
Topics: Animals; Humans; Cachexia; Muscle, Skeletal; Adrenergic Agents; Quality of Life; Neoplasms; Autonomic Nervous System Diseases
PubMed: 38071925
DOI: 10.1016/j.autneu.2023.103136 -
International Journal of Molecular... Nov 2023Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs' associated risk factors to facilitate early detection and... (Review)
Review
Uterine fibroids (UFs) are common tumors in women of reproductive age. It is imperative to comprehend UFs' associated risk factors to facilitate early detection and prevention. Simple relying on surgical/pharmacological treatment of advanced disease is not only highly expensive, but it also deprives patients of good quality of life (QOL). Unfortunately, even if the disease is discovered early, no medical intervention is traditionally initiated until the disease burden becomes high, and only then is surgical intervention performed. Furthermore, after myomectomy, the recurrence rate of UFs is extremely high with the need for additional surgeries and other interventions. This confused approach is invasive and extremely costly with an overall negative impact on women's health. Secondary prevention is the management of early disease to slow down its progression or even halt it completely. The current approach of watchful observation for early disease is considered a major missed opportunity in the literature. The aim of this article is to present an approach named the ESCAPE (Evidence-Based Approach for Secondary Prevention) of UF management. It comprises simple, inexpensive, and safe steps that can arrest the development of UFs, promote overall reproductive health, decrease the number of unnecessary surgeries, and save billions of health care systems' dollars worldwide.
Topics: Humans; Female; Quality of Life; Uterine Neoplasms; Secondary Prevention; Leiomyoma; Uterine Myomectomy
PubMed: 37958957
DOI: 10.3390/ijms242115972 -
Journal of Cachexia, Sarcopenia and... Aug 2023Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms...
BACKGROUND
Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia.
METHODS
In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting.
RESULTS
Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat-free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: -35%, soleus: -49%, extensor digitorum longus: -48%) and the heart (-29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6K (mTORC1 substrate) and ACC (AMPK substrate) and rescued cancer-induced insulin intolerance.
CONCLUSIONS
Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK-deficient mice developing metabolic dysfunction in response to cancer, including AMPK-dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and possibly cachexia.
Topics: Humans; Mice; Male; Animals; Adenosine Monophosphate; AMP-Activated Protein Kinases; Carcinoma, Non-Small-Cell Lung; Cachexia; Lung Neoplasms; Glucose; Muscle, Skeletal; Insulin
PubMed: 37194385
DOI: 10.1002/jcsm.13238 -
Journal of Translational Medicine Aug 2023Currently, women around the world are still suffering from various female common diseases with the high incidence, such as ovarian cancer, uterine fibroids and... (Review)
Review
Currently, women around the world are still suffering from various female common diseases with the high incidence, such as ovarian cancer, uterine fibroids and preeclampsia (PE), and some diseases are even with the high mortality rate. As a negative feedback regulator in G Protein-Coupled Receptor signaling (GPCR), the Regulator of G-protein Signaling (RGS) protein family participates in regulating kinds of cell biological functions by destabilizing the enzyme-substrate complex through the transformation of hydrolysis of G Guanosine Triphosphate (GTP). Recent work has indicated that, the Regulator of G-protein Signaling 2 (RGS2), a member belonging to the RGS protein family, is closely associated with the occurrence and development of certain female diseases, providing with the evidence that RGS2 functions in sustaining women's health. In this review paper, we summarize the current knowledge of RGS2 in female common diseases, and also tap and discuss its therapeutic potential by targeting multiple mechanisms.
Topics: Pregnancy; Humans; Female; Women's Health; Signal Transduction; Hydrolysis; Knowledge; Leiomyoma; RGS Proteins
PubMed: 37649067
DOI: 10.1186/s12967-023-04462-3 -
Cancer Epidemiology, Biomarkers &... Oct 2023Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178...
BACKGROUND
Despite evidence that low muscle increases the risk of chemotoxicity, most chemotherapies are dosed on body surface area without considering body composition. Among 178 patients with colon cancer, we assessed muscle and adipose tissue with multiple techniques and examined their associations with relative dose intensity (RDI) and adverse events.
METHODS
We estimated (i) cross-sectional skeletal muscle area (SMA) and total adipose tissue (TAT) area at L3 from computed tomography (CT); (ii) appendicular lean mass (ALM) and total body fat (TBF) mass from dual-energy X-ray absorptiometry (DXA); and (iii) total body skeletal muscle mass using D3-creatine (D3Cr) dilution. We standardized each measurement by its sex-specific standard deviation (SD). The primary outcome was reduced RDI (RDI <85%). The secondary outcome was the number of moderate and severe adverse events during each cycle of chemotherapy. We estimated the associations of muscle and adipose tissue measurements (per SD increase) with reduced RDI using logistic regression and adverse events using generalized estimating equations for repeated measures.
RESULTS
Higher CT SMA and DXA ALM were significantly associated with a lower risk of reduced RDI [odds ratios: 0.56 (0.38-0.81) for CT SMA; 0.56 (0.37-0.84) for DXA ALM]. No measurements of muscle or adipose tissue were associated with adverse events.
CONCLUSIONS
More muscle was associated with improved chemotherapy completion among patients with colon cancer, whereas muscle and adipose tissue were not associated with adverse events.
IMPACT
Considering body composition may help personalize dosing for colon cancer chemotherapy by identifying patients at risk for poor chemotherapy outcomes.
Topics: Male; Female; Humans; Cross-Sectional Studies; Body Composition; Adipose Tissue; Colonic Neoplasms; Muscle, Skeletal
PubMed: 37450841
DOI: 10.1158/1055-9965.EPI-23-0227