Tyrosine kinase inhibitor-induced hypothyroidism: mechanism and clinical implications.

INTRODUCTION: Since the first experimentally proven tyrosine kinase inhibitor (TKI) imatinib was introduced in the clinical setting, TKIs have attracted widespread attention because of their remarkable therapeutic effects and improvement of survival rates. TKIs are small-molecule, multi-target, anti-cancer agents that target different tyrosine kinases and block downstream signaling. ADVERSE REACTIONS AND CONCERNS: However, with in-depth research on TKI drugs, the adverse reactions-for example, thyroid dysfunction-have become a concern and thus have attracted the attention of numerous researchers. Thyroid dysfunction, especially hypothyroidism, that occurs in high incidence during TKI therapy has a close relationship with treatment efficacy, but the mechanism of TKI-induced thyroid dysfunction is obscure. DISCUSSION: This review discusses the epidemiology, possible mechanisms, and clinical significance of hypothyroidism in cancer patients treated with TKI.

Role of m6A RNA methylation in the development of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy that can be developed from hepatitis B and cirrhosis. Many pathophysiological alterations, including hepatitis B virus (HBV) DNA integration, oxidative stress, cytokine release, telomerase homeostasis, mitochondrial damage, epigenetic modification, and tumor microenvironment, are involved in the biological process from hepatitis B to cirrhosis and HCC. N6-methyladenosine (m6A), as an epitranscriptomic modification of RNAs, can regulate the stability, splicing, degradation, transcription, and translation of downstream target RNAs in HBV and liver cancer cells. m6A regulators (writers, erasers, and readers) play an important role in the pathogenesis of HBV-associated HCC by regulating cell proliferation, apoptosis, migration, autophagy, differentiation, inflammation, angiogenesis, and tumor microenvironment. This review summarizes the current progress of m6A methylation in the molecular mechanisms, biological functions, and potential clinical implications of HBV-associated HCC.

Antioxidant, immunomodulatory, and anti-inflammatory effects of Spirulina in disease conditions: a systematic review.

The goal of this review was to critically evaluate the research on the effects of Spirulina (SP) supplementation on pathological conditions in the general population, considering its antioxidant, immunomodulatory, and anti-inflammatory properties. On a total of 1621 records screened, eighteen studies published between 2001 and 2020 met the inclusion criteria. Despite variability in research methodology and patient conditions, the findings of these studies generally support the benefits of supplementing diet with SP in subjects with both transmittable and non-transmittable diseases. Improvements were found for all the conditions studied, with the only exception of male infertility. However, the number of clinically controlled trials examining the effects of SP on specific health conditions is still very low, and some studies show medium quality. Further research in this field is needed to confirm the possible clinical role of Spirulina supplementation in parallel with medical therapies.

Role of MicroRNA-7 (MiR-7) in Cancer Physiopathology.

miRNAs are non-coding RNA sequences of approximately 22 nucleotides that interact with genes by inhibiting their translation through binding to their 3' or 5' UTR regions. Following their discovery, the role they play in the development of various pathologies, particularly cancer, has been studied. In this context, miR-7 is described as an important factor in the development of cancer because of its role as a tumor suppressor, regulating a large number of genes involved in the development and progression of cancer. Recent data support the function of miR-7 as a prognostic biomarker in cancer, and miR-7 has been proposed as a strategy in cancer therapy. In this work, the role of miR-7 in various types of cancer is reviewed, illustrating its regulation, direct targets, and effects, as well as its possible relationship to the clinical outcome of cancer patients.

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte.

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

Fibronectin and colorectal cancer: signaling pathways and clinical implications.

Colorectal cancer (CRC) is the fourth leading cause of cancer deaths worldwide, with poor prognosis mainly related to metastasis. Fibronectin (FN), a vital component of the extracellular matrix (ECM), has been found involved in tumorigenesis and malignant progression in different types of malignancy. Numerous studies have indicated the distinct expression of FN in various cancers and demonstrated the different functions of FN in the proliferation, migration, and invasion of cancers. Meanwhile, FN isoforms have been extensively used for targeted drug delivery and imaging for tumors. Although a growing number of studies on FN in CRC have been reported, integrated reviews on the relationship between FN and CRC are rare. In this review, we will summarize the association between FN and CRC, including the signaling pathways and molecules involved in, as well as potential diagnostic and therapeutic values of FN for patients with CRC.

Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-of-function mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.

Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate.

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of TMPRSS2-ERG gene fusions and PTEN loss, increased percentage of genomic instability, and higher prevalence of germline BRCA2 mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate-ribose) polymerase inhibitors for patients harboring increased genomic instability or BRCA2 mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor.

Role of epigenetics in lung cancer heterogeneity and clinical implication.

Lung cancer, as a highly heterogeneous disease, can be initiated and progressed through the interaction between permanent genetic mutations and dynamic epigenetic alterations. However, the mediating mechanisms of epigenetics in cancer heterogeneity remain unclear. The evolution of cancer, the existence of cancer stem cells (CSCs) and the phenomenon of epithelial-mesenchymal transition (EMT) have been reported to be involved in lung cancer heterogeneity. In this review, we briefly recap the definition of heterogeneity and concept of epigenetics, highlight the potential roles and mechanisms of epigenetic regulation in heterogeneity of lung cancer, and summarize the diagnostic and therapeutic implications of epigenetic alterations in lung cancer, especially the role of DNA methylation and histone acetylation. Deep understanding of epigenetic regulation in cancer heterogeneity is instrumental to the design of novel therapeutic approaches that target lung cancer.

Clinical implications of a novel prognostic factor AIFM3 in breast cancer patients.

BACKGROUND: In a time of increasing concerns over personalized and precision treatment in breast cancer (BC), filtering prognostic factors attracts more attention. Apoptosis-Inducing Factor Mitochondrion-associated 3 (AIFM3) is widely expressed in various tissues and aberrantly expressed in several cancers. However, clinical implication of AIFM3 has not been reported in BC. The aim of the study is to investigate the crystal structure, clinical and prognostic implications of AIFM3 in BC. METHODS: AIFM3 expression in 151 BC samples were assessed by immunohistochemistry (IHC). The Cancer Genome Atlas (TCGA) and Kaplan-Meier survival analysis were used to demonstrate expression and survival of AIFM3 signature. Gene Set Enrichment Analysis (GSEA) was performed to investigate the mechanisms related to AIFM3 expression in BC. RESULTS: AIFM3 was significantly more expressed in breast cancer tissues than in normal tissues. AIFM3 expression had a significant association with tumor size, lymph node metastasis, TNM stage and molecular typing. Higher AIFM3 expression was related to a shorter overall survival (OS) and disease-free survival (DFS). Lymph node metastasis and TNM stage were independent factors of AIFM3 expression. The study presented the crystal structure of AIFM3 successfully and predicted several binding sites when AIFM3 bonded to PTPN12 by Molecular Operating Environment software (MOE). CONCLUSIONS: AIFM3 might be a potential biomarker for predicting prognosis in BC, adding to growing evidence that AIFM3 might interact with PTPN12.

Circular RNA: new star, new hope in cancer.

BACKGROUND: Circular RNAs are a new class of endogenous non-coding RNA that can function as crucial regulators of diverse cellular processes. The diverse types of circular RNAs with varying cytogenetics in cancer have also been reported. Circular RNAs can act as a microRNA sponge or through other mechanisms to regulate gene expression as either tumor inhibitors or accelerators, suggesting that circular RNAs can serve as newly developed biomarkers with clinic implications. Here, we summerized recent advances on circular RNAs in cancer and described a circular RNA network associated with tumorigenesis. The clinical implications of circular RNAs in cancer were also discussed in this paper. SHORT CONCLUSION: Growing evidence has revealed the crucial regulatory roles of circular RNAs in cancer and the elucidation of functional mechanisms involving circular RNAs would be helpful to construct a circRNA-miRNA-mRNA regulatory network. Moreover, circular RNAs can be easily detected due to their relative stability, widespread expression, and abundance in exosomes, blood and saliva; thus, circular RNAs have potential as new and ideal clinical biomarkers in cancer.

The facial artery: A Comprehensive Anatomical Review.

The facial artery is the major vessel supplying blood to the face so its location and course are very important for the safe manipulation of both surgical and non-surgical interventions. This study documents current anatomical information about the facial artery and its tributaries. The terminology of the facial artery tributaries was revisited with reference to the Terminologica Anatomica and novel nomenclature was suggested with anatomical features. The tributaries to the lower lip (inferior labial artery), labiomental region (horizontal and vertical labiomental artery), upper lip (superior labial artery), nose (inferior and lateral alar artery and nasal septal artery), angular and ocular region (angular artery and detoured branch) and the course, layers and location of the facial artery main trunk were revisited with contemporary anatomical studies. The facial artery and its tributaries have close topographical connections to the facial expression muscles, nasolabial groove, and vermilion border, and these also distinguish facial landmarks comprising the cheilion, stomion, and gonion. Interestingly, in contrast to previous descriptions, some terminal branches did not take a straight course but a detoured course. The angular artery was connected to the ophthalmic artery branches and in some cases did not originate from the facial artery. Vascular complications of the facial artery tributaries are frequently seen in the angular, dorsum of the nose, tip of the nose, and glabellar region. This detailed review focusing on facial arterial topography in the various areas of the face would help to enhance quality of treatment. Clin. Anat. 31:99-108, 2018. © 2017 Wiley Periodicals, Inc.

Cardiovascular responses to sugary drinks in humans: galactose presents milder cardiac effects than glucose or fructose.

PURPOSE: There is increasing interest into the potentially beneficial effects of galactose for obesity and type 2 diabetes management as it is a low-glycemic sugar reported to increase satiety and fat mobilization. However, fructose is also a low-glycemic sugar but with greater blood pressure elevation effects than after glucose ingestion. Therefore, we investigated here the extent to which the ingestion of galactose, compared to glucose and fructose, impacts upon haemodynamics and blood pressure. METHODS: In a randomized cross-over study design, 9 overnight-fasted young men attended 3 separate morning sessions during which continuous cardiovascular monitoring was performed at rest for at least 30 min before and 120 min after ingestion of 500 mL of water containing 60 g of either glucose, fructose or galactose. These measurements included beat-to-beat systolic and diastolic blood pressure, heart rate deduced by electrocardiography, and stroke volume derived by impedance cardiography; these measurements were used to calculate cardiac output and total peripheral resistance. RESULTS: Ingestion of galactose, like glucose, led to significantly lesser increases in systolic, diastolic and mean blood pressure than fructose ingestion (p < 0.05). Furthermore, the increase in cardiac output and reduction in total peripheral resistance observed after ingestion of glucose were markedly lower after galactose ingestion (p < 0.01). CONCLUSIONS: Galactose thus presents the interesting characteristics of a low-glycemic sugar with mild cardiovascular effects. Further studies are warranted to confirm the clinical relevance of the milder cardiovascular effects of galactose than other sugars for insulin resistant obese and/or diabetic patients with cardiac insufficiency.

Expression and clinical implication of S100A12 in gastric carcinoma.

S100 protein family has been implicated in multiple stages of tumorigenesis and progression in which S100A12 is one of the subtypes. However, the role of S100A12 in gastric carcinoma (GC) has not been elucidated yet. This study was aimed to investigate the expression of S100A12 in GC tissues and evaluate the clinical significance of S100A12 in GC patients. S100A12 protein was detected in 207 GC and 52 paired non-cancerous mucosal tissues by immunohistochemistry, while messenger RNA (mRNA) was investigated by Oncomine database analysis. Moreover, survival analysis was performed and the correlation between S100A12 and ubiquitin-specific protease 10 (USP10) and p53 was determined. As for tumor cells, the expression of S100A12 protein and mRNA in GC was proved to be lower than that in non-cancerous mucosa tissues (p < 0.05). Clinicopathological analysis showed that S100A12 protein was negatively associated with tumor size (p = 0.004), depth of invasion (p = 0.022), tumor node metastasis (TNM) stage (p = 0.018), Lauren classification (p < 0.000), and cell differentiation (p < 0.000). In contrast, a positive correlation was found between S100A12 and USP10 protein (p < 0.000). However, no relationship was detected between S100A12 and p53. Moreover, the survival analysis indicated that S100A12 protein was a favorable factor of prognosis of GC (p < 0.05). Although the expression of S100A12 in the stromal cells was detected higher than that in the tumor cells, no relationship between S100A12 protein in stromal cells and the clinicopathological features described above was found (p > 0.05). Our findings suggested that low expression of S100A12 might be served as a new marker in the tumorigenesis and progression of GC.

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications.

Pancreatic cancer is one of the most aggressive human cancer types with a five-year survival less than 7%. Emerging evidence revealed that many genetic alterations in pancreatic cancer target epigenetic regulators. Some of these mutations are driver mutations in cancer development. Several most important mechanisms of epigenetic regulations include DNA methylation, histone modifications (methylation, acetylation, and ubiquitination), chromatin remodeling, and non-coding ribonucleic acids (RNAs). These modifications can alter chromatin structure and promoter accessibility, and thus lead to aberrant gene expression. However, exactly how these alterations affect epigenetic reprogramming in pancreatic cancer cells and in different stages of tumor development is still not clear. This mini-review summarizes the current knowledge of epigenetic alterations in pancreatic cancer development and progression, and discusses the clinical applications of epigenetic regulators as diagnostic biomarkers and therapeutic targets in pancreatic cancer.

Unraveling olfactory subtypes in Parkinson's disease and their effect on the natural history of the disease.

BACKGROUND: Hyposmia in Parkinson's disease (PD) had been studied before but had not been detailed by its temporal progression. This study observed how each olfactory subtype evolved in terms of motor symptoms, cardiac sympathetic innervation, and cognition. METHODS: Two hundred and three early PD patients were classified as normosmia, hyposmia-converter (hypo-converter), and hyposmia. Their presynaptic monoamine availability at the time of diagnosis was assessed by positron emission tomography imaging using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and compared across the subtypes. Motor symptoms were evaluated in all patients, cardiac denervation was examined in 183 patients, and cognition in 195 patients were assessed using a neuropsychological battery. The domains were re-assessed 2-4 times, and the longitudinal data were analyzed to discern the natural course of each subtype. RESULTS: Twenty-nine (14.3%) patients belonged to the normosmia group, 34 (16.7%) to the hypo-converter group, and the rest to the hyposmia (69.0%) group. 85.7% of the total population became hyposmic during an average 3 years of follow-up. The baseline motor symptoms, cardiac denervation, and cognition were comparable across the olfactory subtypes. Across the subtypes, a decline in the presynaptic monoamine densities of the caudate, especially the ventral-anterior subdivisions, correlated inversely with olfaction dysfunction. Over time, motor and cardiac denervation burdens worsened regardless of olfactory subtypes, but hypo-converters experienced faster cognitive deterioration than the other two groups. CONCLUSIONS: The results suggest that the olfactory subtypes have differential significance along the disease course, which might reflect the involvement of different neuro-biochemical circuitries.

Roles of extracellular vesicles derived from healthy and obese adipose tissue in inter-organ crosstalk and potential clinical implication.

Extracellular vesicles (EVs) are nanovesicles containing bioactive molecules including proteins, nucleic acids and lipids that mediate intercellular and inter-organ communications, holding promise as potential therapeutics for multiple diseases. Adipose tissue (AT) serves as a dynamically distributed energy storage organ throughout the body, whose accumulation leads to obesity, a condition characterized by infiltration with abundant immune cells. Emerging evidence has illustrated that EVs secreted by AT are the novel class of adipokines that regulate the homeostasis between AT and peripheral organs. However, most of the studies focused on the investigations of EVs derived from adipocytes or adipose-derived stem cells (ADSCs), the summarization of functions in cellular and inter-organ crosstalk of EVs directly derived from adipose tissue (AT-EVs) are still limited. Here, we provide a systemic summary on the key components and functions of EVs derived from healthy adipose tissue, showing their significance on the tissue recovery and metabolic homeostasis regulation. Also, we discuss the harmful influences of EVs derived from obese adipose tissue on the distal organs. Furthermore, we elucidate the potential applications and constraints of EVs from healthy patients lipoaspirates as therapeutic agents, highlighting the potential of AT-EVs as a valuable biological material with broad prospects for future clinical use.

p38 Molecular Targeting for Next-Generation Multiple Myeloma Therapy.

Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible for the mechanisms of resistance to cancer treatment and progression, and multiple myeloma is no exception. p38 mitogen-activated protein kinase (p38) is downstream of several signaling pathways specific to treatment resistance and progression. Therefore, in recent years, developing therapeutic alternatives directed at p38 has been of great interest, in order to reverse chemotherapy resistance and prevent progression. In this review, we discuss recent findings on the role of p38, including recent advances in our understanding of its expression and activity as well as its isoforms, and its possible clinical role based on the mechanisms of resistance and progression in multiple myeloma.

Traditional Chinese Medicine for Hashimoto's Thyroiditis: Focus on Selenium and Antioxidant Phytochemicals.

Hashimoto's thyroiditis (HT) is not only the most frequent autoimmune thyroid disease (AITD), but it also has a significant impact on patients' health-related quality of life (HRQoL), and it has been variably associated with differentiated thyroid carcinoma. Even though its pathogenesis is still incompletely understood, oxidative stress is believed to play an important role. Hypothyroidism related to later stages of HT can be treated with levothyroxine substitution therapy; various approaches such as selenium supplementation and iodine-restricted diets have been proposed as disease-modifying treatments for earlier stages, and even thyroidectomy has been suggested for refractory cases of painful HT. Nevertheless, many patients still report suboptimal HRQoL, highlighting an unmet medical need in this area. The concepts and approaches of traditional Chinese medicine (TCM) in treating HT are not broadly known in the West. Here, we provide an overview of TCM for HT, including combinations of TCM with selenium. We encompass evidence from clinical trials and other studies related to complex TCM prescriptions, single herbs used in TCM, and phytochemicals; wherever possible, we delineate the probable underlying molecular mechanisms. The findings show that the main active components of TCM for HT have commonly known or presumed antioxidant and anti-inflammatory activities, which may account for their potential utility in HT. Further exploring the practices of TCM for HT and combining them with evidence- and mechanism-based approaches according to Western standards may help to identify new strategies to alter the clinical course of the disease and/or to treat patients' symptoms better and improve their HRQoL.

Comparison of Traditional Impression and 3D Ear Scanning Techniques, Earmold Comfort, and Audiology Clinical Implications: A Pilot Study.

This study investigated clinical aspects of the traditional ear impression and 3D ear scanning techniques. Adult earmold-users and non-users participated in this study. The earmold-users also participated in the earmold comfort comparison study by wearing earmolds from both techniques, one set a week according to a randomized sequence. Multiple clinical aspects of both techniques according to the participants and audiology professionals were recorded. Results revealed a preference for the 3D-scanning technique, which was perceived as more comfortable although both techniques were perceived as safe. Although the earmolds might have issues from both techniques, there was no significant difference in the perception of earmolds. Experience with the specific technique can affect the responses from the professionals. Compared to the traditional technique, 3D-scans had higher fixed but less variable costs and procedure times. A special clinical case was included and indicated that 3D-scans could be an option for specific patients. This study led to a better understanding of the two techniques clinically. With increasing involvement of new technology and more young professionals joining the profession of audiology, 3D ear scanning could be a viable consideration for audiology practices.