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Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.

Extracellular proteolysis is frequently dysregulated in disease and can generate proteoforms with unique neoepitopes not found in healthy tissue. Here, we demonstrate that Abs that selectively recognize a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) could enable more effective and safer treatments for solid tumors. CDCP1 is highly overexpressed in RAS-driven cancers, and its ectodomain is cleaved by extracellular proteases. Biochemical, biophysical, and structural characterization revealed that the 2 cleaved fragments of CDCP1 remain tightly associated with minimal proteolysis-induced conformational change. Using differential phage display, we generated recombinant Abs that are exquisitely selective to cleaved CDCP1 with no detectable binding to the uncleaved form. These Abs potently targeted cleaved CDCP1-expressing cancer cells as an Ab-drug conjugate, an Ab-radionuclide conjugate, and a bispecific T cell engager. In a syngeneic pancreatic tumor model, these cleaved-specific Abs showed tumor-specific localization and antitumor activity with superior safety profiles compared with a pan-CDCP1 approach. Targeting proteolytic neoepitopes could provide an orthogonal "AND" gate for improving the therapeutic index.

Objective Dysphagia is a common clinical condition characterized by difficulty in swallowing. It is sub-classified into oropharyngeal dysphagia, which refers to problems in the mouth and pharynx, and esophageal dysphagia, which refers to problems in the esophageal body and esophagogastric junction. Dysphagia can have a significant negative impact one’s physical health and quality of life as its severity increases. Therefore, proper assessment and management of dysphagia are critical for improving swallowing function and preventing complications. Thus a guideline was developed to provide evidence-based recommendations for assessment and management in patients with dysphagia. Methods Nineteen key questions on dysphagia were developed. These questions dealt with various aspects of problems related to dysphagia, including assessment, management, and complications. A literature search for relevant articles was conducted using Pubmed, Embase, the Cochrane Library, and one domestic database of KoreaMed, until April 2021. The level of evidence and recommendation grade were established according to the Grading of Recommendation Assessment, Development and Evaluation methodology. Results Early screening and assessment of videofluoroscopic swallowing were recommended for assessing the presence of dysphagia. Therapeutic methods, such as tongue and pharyngeal muscle strengthening exercises and neuromuscular electrical stimulation with swallowing therapy, were effective in improving swallowing function and quality of life in patients with dysphagia. Nutritional intervention and an oral care program were also recommended. Conclusion This guideline presents recommendations for the assessment and management of patients with oropharyngeal dysphagia, including rehabilitative strategies.

The goal of the 8th edition of the Clinical Practice Guidelines for Obesity is to help primary care physician provide safe, effective care to patients with obesity by offering evidence-based recommendations to improve the quality of treatment. The Committee for Clinical Practice Guidelines comprised individuals with multidisciplinary expertise in obesity management. A steering board of seven experts oversaw the entire project. Recommendations were developed as the answers to key questions formulated in patient/problem, intervention, comparison, outcomes (PICO) format. Guidelines underwent multi-level review and cross-checking and received endorsement from relevant scientific societies. This edition of the guidelines includes criteria for diagnosing obesity, abdominal obesity, and metabolic syndrome; evaluation of obesity and its complications; weight loss goals; and treatment options such as diet, exercise, behavioral therapy, pharmacotherapy, and bariatric and metabolic surgery for Korean people with obesity. Compared to the previous edition of the guidelines, the current edition includes five new topics to keep up with the constantly evolving field of obesity: diagnosis of obesity, obesity in women, obesity in patients with mental illness, weight maintenance after weight loss, and the use of information and communication technology-based interventions for obesity treatment. This edition of the guidelines features has improved organization, more clearly linking key questions in PICO format to recommendations and key references. We are confident that these new Clinical Practice Guidelines for Obesity will be a valuable resource for all healthcare professionals as they describe the most current and evidence-based treatment options for obesity in a well-organized format.

The endocannabinoid system (ECS) is comprised of a set of lipid-derived messengers (the endocannabinoids, ECBs), proteins that control their production and degradation, and cell-surface cannabinoid (CB) receptors that transduce their actions. ECB molecules such as 2-arachidonoyl-sn-glycerol (2-AG) and anandamide (arachidonoyl ethanolamide) are produced on demand and deactivated through enzymatic actions tightly regulated both temporally and spatially, serving homeostatic roles in order to respond to various challenges to the body. Key components of the ECS are present in the hypothalamus-pituitarygonadal (HPG) axis, which plays critical roles in the development and regulation of the reproductive system in both males and females. ECB signaling controls the action at each stage of the HPG axis through CB receptors expressed in the hypothalamus, pituitary, and reproductive organs such as the testis and ovary. It regulates the secretion of hypothalamic gonadotropinreleasing hormone (GnRH), pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), estrogen, testosterone, and affects spermatogenesis in males. Δ9-tetrahydrocannabinol (THC) and other phytocannabinoids from Cannabis sativa affect a variety of physiological processes by altering, or under certain conditions hijacking, the ECB system. Therefore, phytocannabinoids, in particular THC, may modify the homeostasis of the HPG axis by altering CB receptor signaling and cause deficits in reproductive function. While the ability of phytocannabinoids, THC and/or cannabidiol (CBD), to reduce pain and inflammation provides promising opportunities for therapeutic intervention for genitourinary and degenerative disorders, important questions remain regarding their unwanted long-term effects. It is nevertheless clear that the therapeutic potential of modulating the ECS calls for further scientific and clinical investigation.

The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer’s disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies, including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau-Tg mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.

Since ancient times, essential oils (EOs) derived from aromatic plants have played a significant role in promoting human health. EOs are widely used in biomedical applications due to their medicinal properties. EOs and their constituents have been extensively studied for treating various health-related disorders, including cancer. Nonetheless, their biomedical applications are limited due to several drawbacks. Recent advances in nanotechnology offer the potential for utilising EO-loaded nanoparticles in the treatment of various diseases. In this aspect, chitosan (CS) appears as an exceptional encapsulating agent owing to its beneficial attributes. This review highlights the use of bioactive EOs and their constituents against breast cancer cells. Challenges associated with the use of EOs in biomedical applications are addressed. Essential information on the benefits of CS as an encapsulant, the advantages of nanoencapsulated EOs, and the cytotoxic actions of CS-based nanoencapsulated EOs against breast cancer cells is emphasised. Overall, the nanodelivery of bioactive EOs employing polymeric CS represents a promising avenue against breast cancer cells in preclinical studies.

Musculoskeletal diseases (MSDs) are characterized as injuries and illnesses that affect the musculoskeletal system. MSDs affect every population worldwide and are associated with substantial global burden. Variations in the makeup of the gut microbiota may be related to chronic MSDs. There is growing interest in exploring potential connections between chronic MSDs and variations in the composition of gut microbiota. The human microbiota is a complex community consisting of viruses, archaea, bacteria, and eukaryotes, both inside and outside of the human body. These microorganisms play crucial roles in influencing human physiology, impacting metabolic and immunological systems in health and disease. Different body areas host specific types of microorganisms, with facultative anaerobes dominating the gastrointestinal tract (able to thrive with or without oxygen), while strict aerobes prevail in the nasal cavity, respiratory tract, and skin surfaces (requiring oxygen for development). Together with the immune system, these bacteria have coevolved throughout time, forming complex biological relationships. Changes in the microbial ecology of the gut may have a big impact on health and can help illnesses develop. These changes are frequently impacted by lifestyle choices and underlying medical disorders. The potential for safety, expenses, and efficacy of microbiota-based medicines, even with occasional delivery, has attracted interest. They are, therefore, a desirable candidate for treating MSDs that are chronic and that may have variable progression patterns. As such, the following is a narrative review to address the role of the human microbiome as it relates to MSDs.

Corneal neovascularization (CoNV) is a sight-threatening condition affecting an estimated 1.4 million people per year, and the incidence is expected to rise. It is a complication of corneal pathological diseases such as infective keratitis, chemical burn, corneal limbal stem cell deficiency, mechanical trauma, and immunological rejection after keratoplasties. CoNV occurs due to a disequilibrium in proangiogenic and antiangiogenic mediators, involving a complex system of molecular interactions. Treatment of CoNV is challenging, and no therapy thus far has been curative. Anti-inflammatory agents such as corticosteroids are the mainstay of treatment due to their accessibility and well-studied safety profile. However, they have limited effectiveness and are unable to regress more mature neovascularization. With the advent of advanced imaging modalities and an expanding understanding of its pathogenesis, contemporary treatments targeting a wide array of molecular mechanisms and surgical options are gaining traction. This review aims to summarize evidence regarding conventional and emerging therapeutic options for CoNV. [ABSTRACT FROM AUTHOR]

Introduction: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. Methods: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011–30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan–Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). Results: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60–72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7–25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0–53.9 days). Median TTD was 9.3 months (95% CI 6.1–11.3 months). Median TTNT was 12.9 months (95% CI 11.5–19.0 months). Conclusions: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC. [ABSTRACT FROM AUTHOR]

Background: Patients receiving palliative care often face psychological distress, which can be challenging for clinicians to manage. Therefore, reflexive and visual journaling can be used as powerful techniques for clinician selfreflection and personal development. These journals are a form of practice wisdom, providing insights into psychological health in palliative care. Aim: This study aims to describe how patients receiving palliative care experience psychological health, explore the meaning of a palliative care clinician's work and contribute to the understanding of psychological health in palliative care through the reflexive and visual journals of clinicians. Design: Using Gibb's reflective cycle as a framework for journaling, this study employs reflexive and visual journaling through the lenses of a psychiatrist and an art therapist. Journal data were analysed using a thematic analysis approach. Setting/participants: The two first authors journaled 107 clinical encounters and created 36 pieces of response art detailing encounters with patients and their families, and clinical conversations in two palliative care centres. Results: Patient attributes and the clinical environment were observed to influence psychological health in palliative care. The patient's ability to navigate dying, maintain personhood, exert resilience and experience satisfying relationships contribute to psychological health. A clinical environment comprising clinicians with holistic competencies, systems promoting interdisciplinary collaborations and a values-based culture that promotes patient centricity strengthens the delivery of psychological care. Conclusions: Good psychological health in palliative care extends beyond psychopathology and is influenced by the cardinal elements of being human, value systems and systemic elements in the therapeutic environment. [ABSTRACT FROM AUTHOR]

The WNT pathway has become an attractive target for skeletal therapies. High-bone-mass phenotypes in patients with loss-of-function mutations in the LRP5/6 inhibitor Sost (sclerosteosis), or in its downstream enhancer region (van Buchem disease), highlight the utility of targeting Sost/sclerostin to improve bone properties. Sclerostin-neutralizing antibody is highly osteoanabolic in animal models and in human clinical trials, but antibody-based inhibition of another potent LRP5/6 antagonist, Dkk1, is largely inefficacious for building bone in the unperturbed adult skeleton. Here, we show that conditional deletion of Dkk1 from bone also has negligible effects on bone mass. Dkk1 inhibition increases Sost expression, suggesting a potential compensatory mechanism that might explain why Dkk1 suppression lacks anabolic action. To test this concept, we deleted Sost from osteocytes in, or administered sclerostin neutralizing antibody to, mice with a Dkk1-deficient skeleton. A robust anabolic response to Dkk1 deletion was manifest only when Sost/sclerostin was impaired. Whole-body DXA scans, μCT measurements of the femur and spine, histomorphometric measures of femoral bone formation rates, and biomechanical properties of whole bones confirmed the anabolic potential of Dkk1 inhibition in the absence of sclerostin. Further, combined administration of sclerostin and Dkk1 antibody in WT mice produced a synergistic effect on bone gain that greatly exceeded individual or additive effects of the therapies, confirming the therapeutic potential of inhibiting multiple WNT antagonists for skeletal health. In conclusion, the osteoanabolic effects of Dkk1 inhibition can be realized if sclerostin upregulation is prevented. Anabolic therapies for patients with low bone mass might benefit from a strategy that accounts for the compensatory milieu of WNT inhibitors in bone tissue.

Glycogen debranching enzyme deficiency in glycogen storage disease type III (GSD III) results in excessive glycogen accumulation in multiple tissues, primarily the liver, heart, and skeletal muscle. We recently reported that an adeno-associated virus vector expressing a bacterial debranching enzyme (pullulanase) driven by the ubiquitous CMV enhancer/chicken β-actin (CB) promoter cleared glycogen in major affected tissues of infant GSD IIIa mice. In this study, we developed a potentially novel dual promoter consisting of a liver-specific promoter (LSP) and the CB promoter for gene therapy in adult GSD IIIa mice. Ten-week treatment with an adeno-associated virus vector containing the LSP-CB dual promoter in adult GSD IIIa mice significantly increased pullulanase expression and reduced glycogen contents in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, improved muscle function, and a significant decrease in plasma biomarkers alanine aminotransferase, aspartate aminotransferase, and creatine kinase. Compared with the CB promoter, the dual promoter effectively decreased pullulanase-induced cytotoxic T lymphocyte responses and enabled persistent therapeutic gene expression in adult GSD IIIa mice. Future studies are needed to determine the long-term durability of dual promoter–mediated expression of pullulanase in adult GSD IIIa mice and in large animal models.

Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2–3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond dermatological manifestations to impact joints and nails and is often associated with systemic disorders. Although traditional treatments provide relief, their use is limited by potential side effects and the chronic nature of the disease. This review aims to discuss the therapeutic potential of keratinocyte-targeting natural products in psoriasis and highlight their efficacy and safety in comparison with conventional treatments. This review comprehensively examines psoriasis pathogenesis within keratinocytes and the various related signaling pathways (such as JAK-STAT and NF-κB) and cytokines. It presents molecular targets such as high-mobility group box-1 (HMGB1), dual-specificity phosphatase-1 (DUSP1), and the aryl hydrocarbon receptor (AhR) for treating psoriasis. It evaluates the ability of natural compounds such as luteolin, piperine, and glycyrrhizin to modulate psoriasis-related pathways. Finally, it offers insights into alternative and sustainable treatment options with fewer side effects. [ABSTRACT FROM AUTHOR]

Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the olfactory acuity and quality of life in patients who have undergone total laryngectomy. The study also aims to identify any specific patient-related risk factors linked to worse olfactory outcomes. Methods: This is a prospective cross-sectional study conducted at the University Malaya Medical Centre. A total of 30 patients who have undergone total laryngectomy were assessed objectively using the Sniffin' Sticks test and compared against normal age-matched Malaysians. Subsequently, they also filled out the modified Questionnaire on Olfactory Disorders. Correlations of patient demographics, disease and treatment variables against olfactory outcomes were conducted. Results: All subjects suffered olfactory impairment, with 66.7% of them being anosmic after total laryngectomy. The Sniffin' Sticks test demonstrated a statistically significant difference between laryngectomees and the normal age-matched Malaysian population in all three subtests for odor threshold, discrimination and identification. 37% of patients developed olfactory adaptive methods, which resulted in higher olfactory scores and a better quality of life. There were no patient demographics, disease or treatment variables associated with a poorer olfactory outcome identified. Conclusion: Olfactory impairment should not be overlooked among patients after total laryngectomy. Although as many as a third of patients developed some sort of olfactory adaptive behavior, early rehabilitation should be integrated into the multidisciplinary rehabilitation program after total laryngectomy. [ABSTRACT FROM AUTHOR]

The ward round (WR) is an important opportunity for interprofessional interaction and communication enabling optimal patient care. Pharmacists' participation in the interprofessional WR can reduce adverse drug events and improve medication appropriateness and communication. WR participation by clinical pharmacists in Australia is currently limited. This study aims to explore what is impacting clinical pharmacists' participation in WRs in Australian hospitals. A self-administered, anonymous national survey of Australian clinical pharmacists was conducted. This study describes the outcomes from qualitative questions which were analyzed thematically in NVivo-2020 according to Braun and Clarke's techniques. Five themes were constructed: "Clinical pharmacy service structure", "Ward round structure", "Pharmacist's capabilities", "Culture" and "Value". A culture supportive of pharmacist's contribution with a consistent WR structure and flexible delivery of clinical pharmacy services enabled pharmacists' participation in WR. Being physically "absent" from the WR due to workload, workflow, and self-perception of the need for extensive clinical knowledge can limit opportunities for pharmacists to proactively contribute to medicines decision-making with physicians to improve patient care outcomes. Bidirectional communication between the interprofessional team and the pharmacist, where there is a co-construction of each individual's role in the WR facilitates consistent and inter-dependent collaborations for effective medication management. [ABSTRACT FROM AUTHOR]

Rationale: Chronic sarcoidosis is a complex granulomatous disease with limited treatment options that can progress over time. Understanding the molecular pathways contributing to disease would aid in new therapeutic development. Objectives: To understand whether macrophages from patients with nonresolving chronic sarcoidosis are predisposed to macrophage aggregation and granuloma formation and whether modulation of the underlying molecular pathways influence sarcoidosis granuloma formation. Methods: Macrophages were cultivated in vitro from isolated peripheral blood CD14+ monocytes and evaluated for spontaneous aggregation. Transcriptomics analyses and phenotypic and drug inhibitory experiments were performed on these monocyte-derived macrophages. Human skin biopsies from patients with sarcoidosis and a myeloid Tsc2-specific sarcoidosis mouse model were analyzed for validatory experiments. Measurements and Main Results: Monocyte-derived macrophages from patients with chronic sarcoidosis spontaneously formed extensive granulomas in vitro compared with healthy control participants. Transcriptomic analyses separated healthy and sarcoidosis macrophages and identified an enrichment in lipid metabolic processes. In vitro patient granulomas, sarcoidosis mouse model granulomas, and those directly analyzed from lesional patient skin expressed an aberrant lipid metabolism profile and contained increased neutral lipids. Conversely, a combination of statins and cholesterol-reducing agents reduced granuloma formation both in vitro and in vivo in a sarcoidosis mouse model. Conclusions: Together, our findings show that altered lipid metabolism in sarcoidosis macrophages is associated with its predisposition to granuloma formation and suggest cholesterol-reducing therapies as a treatment option in patients. [ABSTRACT FROM AUTHOR]

Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single‐cell RNA sequencing (scRNA‐seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor‐associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF‐1α destabilization, leading to reduction in M2‐like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN‐response genes. Expression of these genes contributed to anti‐tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT‐initiated TAM‐specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression. [ABSTRACT FROM AUTHOR]

The G protein–coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-β1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-β1–induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.

Extracellular proteolysis is frequently dysregulated in disease and can generate proteoforms with unique neoepitopes not found in healthy tissue. Here, we demonstrate that Abs that selectively recognize a proteolytic neoepitope on CUB domain containing protein 1 (CDCP1) could enable more effective and safer treatments for solid tumors. CDCP1 is highly overexpressed in RAS-driven cancers, and its ectodomain is cleaved by extracellular proteases. Biochemical, biophysical, and structural characterization revealed that the 2 cleaved fragments of CDCP1 remain tightly associated with minimal proteolysis-induced conformational change. Using differential phage display, we generated recombinant Abs that are exquisitely selective to cleaved CDCP1 with no detectable binding to the uncleaved form. These Abs potently targeted cleaved CDCP1-expressing cancer cells as an Ab-drug conjugate, an Ab-radionuclide conjugate, and a bispecific T cell engager. In a syngeneic pancreatic tumor model, these cleaved-specific Abs showed tumor-specific localization and antitumor activity with superior safety profiles compared with a pan-CDCP1 approach. Targeting proteolytic neoepitopes could provide an orthogonal “AND” gate for improving the therapeutic index.

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups—hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.

Background: Peripheral T-cell lymphomas (PTCLs) are uncommon and their frequency is regionally heterogeneous. Several studies have been conducted to evaluate the clinical features and treatment outcomes of this disease entity, but the majority of these were conducted in limited areas, making it difficult to comprehensively analyze their relative frequency and clinical features. Furthermore, no consensus treatment for PTCLs has been established. Therefore, we conducted an Asia-specific study to understand the relative frequency of PTCLs and assess treatments and their outcomes in Asian patients. Methods: We performed a multinational, multicenter, prospective registry of adult patients with PTCLs that was named as the International Cooperative non-Hodgkin T-cell lymphoma prospective registry study where thirty-two institutes from six Asian countries and territories (Korea, China, Taiwan, Singapore, Malaysia, and Indonesia) participated. Findings: A total of 486 patients were registered between April 2016 and February 2019, and more than a half of patients (57%) had stage III or IV. Extranodal natural killer (NK)/T- cell lymphoma was the most common subtype (n = 139,28.6%), followed by angioimmunoblastic T-cell lymphoma (AITL, n = 120,24.7%), PTCL-not otherwise specified (PTCL-NOS, n = 101,20.8%), ALK-positive anaplastic large cell lymphoma (ALCL, n = 34,6.9%), and ALK-negative ALCL (n = 30,6.2%). The median progression-free survival (PFS) and overall survival (OS) were 21.1 months (95% CI,10.6–31.6) and 83.6 months (95% CI, 56.7–110.5), respectively. Upfront use of combined treatment with chemotherapy and radiotherapy showed better PFS than chemotherapy alone in localized ENKTL whereas consolidation with upfront autologous stem cell transplantation (SCT) provided longer PFS in advance stage ENKTL. In patients with PTCLs other than ENKTL, anthracycline-containing chemotherapies were widely used, but the outcome of those regimens was not satisfactory, and upfront autologous SCT was not significantly associated with survival benefit, either. The treatment outcome of salvage chemotherapy was disappointing, and none of the salvage strategies showed superiority to one another. Interpretation: This multinational, multicenter study identified the relative frequency of each subtype of PTCLs across Asian countries, and the survival outcomes according to the therapeutic strategies currently used. Funding: Samsung Biomedical Research Institute

Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.

Background: Chronic limb-threatening ischaemia can be a debilitating disease and may result in limb amputation if untreated. Atherosclerotic disease of the infra-popliteal arteries is particularly challenging to treat due to the small caliber of the vessels and the heavy burden of atherosclerotic plaque. Percutaneous transluminal angioplasty is the conventional first-line approach and is advantageous due to its minimal invasiveness, repeatability, and cost-effectiveness but is limited by high rates of elastic recoil, dissection, and short- to mid-term re-stenosis. Methods: This review analyses the growing body of published and presented clinical data from multiple randomised controlled trials that have investigated the role of coronary drug-eluting stents in the treatment of infrapopliteal disease. Results: Coronary drug-eluting stents demonstrate superior primary patency compared with angioplasty and/or bare metal stenting alone but are limited to application in short-segment disease and have not been widely adopted due to the nature of the permanent implant. Conclusions: Newer devices like drug-eluting resorbable scaffolds are promising as they allow the restoration of vessel wall vasomotion without a residual foreign body and can be used to treat longer, complex lesions. [ABSTRACT FROM AUTHOR]

Since ancient times, essential oils (EOs) derived from aromatic plants have played a significant role in promoting human health. EOs are widely used in biomedical applications due to their medicinal properties. EOs and their constituents have been extensively studied for treating various health-related disorders, including cancer. Nonetheless, their biomedical applications are limited due to several drawbacks. Recent advances in nanotechnology offer the potential for utilising EO-loaded nanoparticles in the treatment of various diseases. In this aspect, chitosan (CS) appears as an exceptional encapsulating agent owing to its beneficial attributes. This review highlights the use of bioactive EOs and their constituents against breast cancer cells. Challenges associated with the use of EOs in biomedical applications are addressed. Essential information on the benefits of CS as an encapsulant, the advantages of nanoencapsulated EOs, and the cytotoxic actions of CS-based nanoencapsulated EOs against breast cancer cells is emphasised. Overall, the nanodelivery of bioactive EOs employing polymeric CS represents a promising avenue against breast cancer cells in preclinical studies. [ABSTRACT FROM AUTHOR]

Tauopathy is characterized by the abnormal aggregation of tau proteins. In order to develop drugs for tauopathies, a variety of different therapeutic strategies have been investigated. Synapse loss is a hallmark of tauopathies and is reportedly related to cognitive impairment in Alzheimer's disease as well. Emerging evidence suggests that pathogenic tau species are linked to synaptic dysfunction and synapse loss in tauopathies. As such, a potential therapeutic approach to ameliorate synaptic dysfunction and counteract synaptic loss due to pathogenic tau holds promise. This review highlights the pathological links between tau pathology and synaptic integrity and current efforts to develop therapeutics rescuing synaptic dysfunction for tauopathies, which will help to understand the association between tau and synapses and develop disease‐modifying drugs for tauopathies. [ABSTRACT FROM AUTHOR]

Purpose In the modern era of precision medicine, next-generation sequencing (NGS) is employed for a variety of clinical purposes. The aim of this study was to investigate the trends and clinical characteristics of NGS testing in South Korea. Materials and Methods This nationwide, population-based, retrospective cohort study examined National Health Insurance Service claims data from 2017 to 2021 for NGS and from 2008 to 2021 for gene-targeted anticancer drugs. Results Among the total 98,748 claims, there were 51,407 (52.1%) solid cancer panels, 30,173 (30.5%) hereditary disease panels, and 17,168 (17.4%) hematolymphoid cancer panels. The number of annual claims showed a persistent upward trend, exhibiting a 5.4-fold increase, from 5,436 in 2017 to 29,557 in 2021. In the solid cancer panel, colorectal cancer was the most common (19.2%), followed by lung cancer (18.8%). The annual claims for targeted cancer drugs have increased 25.7-fold, from 3,932 in 2008 to 101,211 in 2020. Drugs for the treatment of lung cancer accounted for 488,819 (71.9%) claims. The number of patients who received non-hereditary NGS testing has substantially increased, and among them, the count of patients prescribed targeted anticancer drugs consistently rose from 508 (13.9%) in 2017 to 2,245 (12.3%) in 2020. Conclusion This study highlights the rising nationwide demand for comprehensive genetic testing for disease diagnosis and treatment following NGS reimbursement by the National Health Insurance in South Korea, in addition to the need for greater utilization of targeted anticancer drugs. [ABSTRACT FROM AUTHOR]

Phytopharmaceuticals have been widely used globally since ancient times and acknowledged by healthcare professionals and patients for their superior therapeutic value and fewer side-effects compared to modern medicines. However, phytopharmaceuticals need a scientific and methodical approach to deliver their components and thereby improve patient compliance and treatment adherence. Dose reduction, improved bioavailability, receptor selective binding, and targeted delivery of phytopharmaceuticals can be likely achieved by molding them into specific nano-formulations. In recent decades, nanotechnology-based phytopharmaceuticals have emerged as potential therapeutic candidates for the treatment of various communicable and non-communicable diseases. Nanotechnology combined with phytopharmaceuticals broadens the therapeutic perspective and overcomes problems associated with plant medicine. The current review highlights the therapeutic application of various nano-phytopharmaceuticals in neurological, cardiovascular, pulmonary, and gastro-intestinal disorders. We conclude that nano-phytopharmaceuticals emerge as promising therapeutics for many pathological conditions with good compliance and higher acceptance.

This document discusses the role of oxidative damage in aging and age-related diseases. It highlights the potential of medicinal herbs in suppressing oxidative damage caused by reactive oxygen species (ROSs) and explores their therapeutic effects in treating age-related diseases. The document presents several studies that demonstrate the antioxidant and anti-inflammatory effects of specific medicinal herbs, such as Euonymus alatus leaf extract, baicalein, and Prunella vulgaris and Gentiana lutea combination. These findings provide valuable insights for researchers and clinicians in developing treatments for aging-related conditions. [Extracted from the article]

Small extracellular vesicles (sEVs) from mesenchymal stromal/stem cells (MSCs) are transiting rapidly towards clinical applications. However, discrepancies and controversies about the biology, functions, and potency of MSC-sEVs have arisen due to several factors: the diversity of MSCs and their preparation; various methods of sEV production and separation; a lack of standardized quality assurance assays; and limited reproducibility of in vitro and in vivo functional assays. To address these issues, members of four societies (SOCRATES, ISEV, ISCT and ISBT) propose specific harmonization criteria for MSC-sEVs to facilitate data sharing and comparison, which should help to advance the field towards clinical applications. Specifically, MSC-sEVs should be defined by quantifiable metrics to identify the cellular origin of the sEVs in a preparation, presence of lipid-membrane vesicles, and the degree of physical and biochemical integrity of the vesicles. For practical purposes, new MSC-sEV preparations might also be measured against a well-characterized MSC-sEV biological reference. The ultimate goal of developing these metrics is to map aspects of MSC-sEV biology and therapeutic potency onto quantifiable features of each preparation.

The coronavirus disease (COVID-19) pandemic poses serious global health concerns with the continued emergence of new variants. The periodic outbreak of novel emerging and re-emerging infectious pathogens has elevated concerns and challenges for the future. To develop mitigation strategies against infectious diseases, nano-based approaches are being increasingly applied in diagnostic systems, prophylactic vaccines, and therapeutics. This review presents the properties of various nanoplatforms and discusses their role in the development of sensors, vectors, delivery agents, intrinsic immunostimulants, and viral inhibitors. Advanced nanomedical applications for infectious diseases have been highlighted. Moreover, physicochemical properties that confer physiological advantages and contribute to the control and inhibition of infectious diseases have been discussed. Safety concerns limit the commercial production and clinical use of these technologies in humans; however, overcoming these limitations may enable the use of nanomaterials to resolve current infection control issues via application of nanomaterials as a platform for the diagnosis, prevention, and treatment of viral diseases.

Acceptance of traditional chinese medicine (TCM) treatment is important in cancer patients to improve treatment efficacy, reduce side effects and prolong prognosis and survival rate. However, such studies and validated instruments that assess the acceptance of TCM treatment in Malaysia are limited. This study aimed to evaluate the validity and reliability of the acceptance of the TCM treatment questionnaire based on applying the Theory of Planned Behaviour. The validation study was conducted in two phases. The first phase included content validation, adaptation and face validity using the Survey Validation Rubric for Expert Panel (VREP). The second phase included construct reliability by using Cronbach alpha. The first phase validation of the questionnaire met expectations from the experts' panel with a score of 3.33. In phase two, 78 patients were included in the analysis. All constructs achieved a Cronbach Alpha >0.8, showing good reliability of the questionnaire. This study demonstrated good validity and reliability of the major constructs in the acceptance of the TCM questionnaire. Our results showed that the acceptance of the TCM questionnaire was a reliable instrument that could be applied to evaluate the acceptance of TCM treatment among cancer patients. [ABSTRACT FROM AUTHOR]

This article, titled "Golden age of immunoengineering," discusses the significant advancements in the field of immunoengineering and its potential for developing disease-modifying therapies. The immune system's role in various diseases, including cancer, autoimmunity, and transplant rejection, is explored. The article highlights the importance of precise control over the immune response and the development of tools and strategies, such as protein and genetic engineering, to enhance the safety, specificity, and efficacy of immunotherapies. The use of cytokines, antibodies, T-cell receptors, and chimeric antigen receptor (CAR) T-cell therapy is discussed, along with the exploration of alternative immune cell sources like natural killer (NK) cells and macrophages. The article also mentions the potential of engineered immune cells in addressing autoimmunity and transplant rejection. Overall, the article emphasizes the immense potential of immunoengineering in revolutionizing disease treatment and the need for multidimensional modulation of the immune system. [Extracted from the article]

PURPOSE Treatment-associated symptoms drive early discontinuation of adjuvant endocrine therapy (ET) for breast cancer. We hypothesized that symptom monitoring with electronic patient-reported outcomes (ePROs) during adjuvant ET will enhance symptom detection, symptom management, and persistence. METHODS Eligible patients were initiating ET for stage 0-III breast cancer. Participants completed ePRO surveys via smartphone at baseline and 1, 3, 6, and 12 months. Measures included Patient-Reported Outcomes Measurement Information System Anxiety, Depression, Fatigue, and Vaginal Discomfort; plus Patient- Reported Outcomes version of the Common Terminology Criteria for Adverse Events items assessing joint pain, hot flashes, vaginal dryness, concentration problems, and memory problems. Scores surpassing prespecified thresholds triggered alerts, and recommended symptom management pathways were provided to clinicians. The primary objective was to evaluate feasibility, assessed by survey completion rates, with targets of >65% for the baseline survey and ≥1 follow-up survey during the first 6 months. Secondary objectives included 12-month ET discontinuation rate (target: ≤15%), describing symptoms and evaluating pathway implementation. RESULTS Among 250 participants, 73.2% completed the baseline survey and 69.6% completed ≥1 follow-up survey during the first 6 months. Thirty-one percent of participants had ≥1 symptom alert at baseline and 74% had ≥1 symptom alert during follow-up. The proportions of participants for whom pathwayconcordant symptom management was documented at each time point ranged from 12.8% to 36.6%. Twenty-eight participants (11.2%) discontinued ET by 12 months. CONCLUSION Symptom monitoring with ePROs during adjuvant ET is feasible. Despite infrequent documentation of pathway-concordant symptom management after symptom alerts, ePROs were associated with favorable short-term ET persistence. [ABSTRACT FROM AUTHOR]

Musculoskeletal diseases (MSDs) are characterized as injuries and illnesses that affect the musculoskeletal system. MSDs affect every population worldwide and are associated with substantial global burden. Variations in the makeup of the gut microbiota may be related to chronic MSDs. There is growing interest in exploring potential connections between chronic MSDs and variations in the composition of gut microbiota. The human microbiota is a complex community consisting of viruses, archaea, bacteria, and eukaryotes, both inside and outside of the human body. These microorganisms play crucial roles in influencing human physiology, impacting metabolic and immunological systems in health and disease. Different body areas host specific types of microorganisms, with facultative anaerobes dominating the gastrointestinal tract (able to thrive with or without oxygen), while strict aerobes prevail in the nasal cavity, respiratory tract, and skin surfaces (requiring oxygen for development). Together with the immune system, these bacteria have coevolved throughout time, forming complex biological relationships. Changes in the microbial ecology of the gut may have a big impact on health and can help illnesses develop. These changes are frequently impacted by lifestyle choices and underlying medical disorders. The potential for safety, expenses, and efficacy of microbiota-based medicines, even with occasional delivery, has attracted interest. They are, therefore, a desirable candidate for treating MSDs that are chronic and that may have variable progression patterns. As such, the following is a narrative review to address the role of the human microbiome as it relates to MSDs. [ABSTRACT FROM AUTHOR]

End stage renal disease (ESRD) patients on renal replacement therapy (RRT) have an increased risk of morbidity and mortality due to healthcare associated infections (HCAIs). The aim of this study is to determine the prevalence, microbial etiology, and risk factors associated with HCAIs among ESRD patients on RRT. A multicenter, retrospective study was conducted from June to December 2019. ESRD patients with minimum of 6 months on RRT were included, while pregnant patients and patients <18 years were excluded. To reduce the risk of selection bias, all patients were randomly selected using a simple random sampling technique. The prevalence showing the proportion of patients that acquired HCAI since the initiation of dialysis until 2019 was calculated using the European patients' academy (EUPATI) formula. Risk factors were assessed using univariate and multivariate regression analysis. The prevalence of HCAI among ESRD patients was 174/400 (43.5%). Catheter related bloodstream infection (CRBSI) was the most common infection [64(36.8%)], followed by peritonitis [45(25.8%)] and pneumonia [37(21.2%)]. Out of 382 total pathogens identified, 204 (53.4%) were Gram positive and 162 (42.4%) were Gram negative. Both methicillin sensitive staphylococcus aureus (MSSA) and methicillin resistant staphylococcus aureus (MRSA) showed statistically significant associations (p<0.05) with CRBSI. Use of multiple accesses, increased blood sugar levels, low serum sodium levels and higher CRP concentration increased the occurrence of HCAIs. The burden of HCAIs among the patients undergoing RRT is high. Preventive strategies and optimum empirical therapy of antibiotics should be used to reduce the risk of these infections among ESRD patients. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), the commonest arthritis, is characterized by the progressive destruction of cartilage, leading to disability. The Current early clinical treatment strategy for OA often centers on anti‐inflammatory or analgesia medication, weight loss, improved muscular function and articular cartilage repair. Although these treatments can relieve symptoms, OA tends to be progressive, and most patients require arthroplasty at the terminal stages of OA. Recent studies have shown a close correlation between joint pain, inflammation, cartilage destruction and synovial cells. Consequently, understanding the potential mechanisms associated with the action of synovial cells in OA could be beneficial for the clinical management of OA. Therefore, this review comprehensively describes the biological functions of synovial cells, the synovium, together with the pathological changes of synovial cells in OA, and the interaction between the cartilage and synovium, which is lacking in the present literature. Additionally, therapeutic approaches based on synovial cells for OA treatment are further discussed from a clinical perspective, highlighting a new direction in the treatment of OA. [ABSTRACT FROM AUTHOR]

Abstract Growing interest in extracellular vesicles (EVs, including exosomes and microvesicles) as therapeutic entities, particularly in stem cell‐related approaches, has underlined the need for standardization and coordination of development efforts. Members of the International Society for Extracellular Vesicles and the Society for Clinical Research and Translation of Extracellular Vesicles Singapore convened a Workshop on this topic to discuss the opportunities and challenges associated with development of EV‐based therapeutics at the preclinical and clinical levels. This review outlines topic‐specific action items that, if addressed, will enhance the development of best‐practice models for EV therapies. Stem Cells Translational Medicine 2017;6:1730–1739

Simple Summary: Polo-like kinase 4 (PLK4) is associated with tumorigenesis and prognosis in various types of cancer. Prognostic analysis of PLK4 expression and data analysis of its association with the somatic mutation and drug resistance through clustering were performed using the Cancer Genome Atlas-lung adenocarcinoma (TCGA-LUAD) dataset. According to these results, PLK4 expression is associated with poor prognosis, TP53 mutations, and drug resistance in patients with LUAD. (1) Background: This study investigated whether polo-like kinase 4 (PLK4) is a suitable therapeutic target or biomarker for lung adenocarcinoma (LUAD). (2) Methods: We acquired LUAD data from The Cancer Genome Atlas (TCGA) database through the UCSC Xena data portal. Gene expression, clinical, survival, and mutation data from multiple samples were analyzed. Gene enrichment analysis, unsupervised clustering of PLK4-related pathways, and differential gene expression analyses were performed. Additionally, correlations, t-tests, survival analyses, and statistical analyses were performed. (3) Results: PLK4 expression was higher in LUAD tissues than in normal tissues and was associated with poor prognosis for both overall and progression-free survival in LUAD. PLK4 was highly correlated with cell-proliferation-related pathways using Gene Ontology (GO) biological process terms. PLK4 expression and pathways that were highly correlated with PLK4 expression levels were upregulated in patients with LUAD with the TP53 mutation. (4) Conclusions: PLK4 expression affects the survival of patients with LUAD and is a potential therapeutic target for LUAD with TP53 mutations. [ABSTRACT FROM AUTHOR]

Background: Idiopathic avascular necrosis of the lunate is known as Kienböck's disease and that of the scaphoid is known as Preiser's disease. Because the prevalence of coexisting Kienböck's and Preiser's diseases is very low, standardized stages of disease and treatments are not established. Case Presentation: We report coexisting avascular necrosis of the scaphoid and lunate in a 68‐year‐old woman with no history of steroids or other risk factors. We treated her with proximal row carpectomy with capsular interposition technique. A distal‐based dorsal capsular flap was prepared and repaired the palmar capsule. At the last follow‐up, she had no pain and had gained improved range of wrist motion. There was no arthritic change at the newly formed radiocapitate joint. Conclusions: In the case of collapsed lunate and scaphoid with avascular necrosis, the proximal row carpectomy procedure has an advantage. Proximal row carpectomy with dorsal capsular interposition can be performed when the lunate or scaphoid cannot be saved. Arthritic changes of the capitate head and distal radius lunate facet can be covered with the dorsal capsule. [ABSTRACT FROM AUTHOR]