Incidence Trends, Clinicopathologic Characteristics, and Overall Survival Prediction in Retinoblastoma Children: SEER Prognostic Nomogram Analysis.

BACKGROUND: Retinoblastoma is the most common intraocular malignant tumor occurring among children, with an incidence rate of 1/15 000. This study built a joinpoint regression model to assess the incidence trend of retinoblastoma from 2004 to 2015 and constructed a nomogram to predict the overall survival (OS) in children. MATERIALS AND METHODS: Patients less than 19 years diagnosed with retinoblastoma from 2004 to 2015 were selected from the SEER database. Joinpoint regression analysis (version 4.9.0.0) was performed to evaluate the trends in retinoblastoma incidence rates from 2004 to 2015. Cox Regression Analysis was applied to investigate prognostic risk factors that influence OS. RESULTS: Joinpoint regression revealed that retinoblastoma incidence exhibited no significant increase or decrease from 2004 to 2015. As per the multiple Cox regression, tumor size, laterality, and residence (rural-urban continuum code) were correlated with OS and were used to construct a nomogram. The nomogram exhibited a good C-index of 0.71 (95% CI, 0.63 to 0.79), and the calibration curve for survival probability demonstrated that the predictions corresponded well with actual observations. CONCLUSIONS AND RELEVANCE: A prognostic nomogram integrating the risk factors for retinoblastoma was constructed to provide comparatively accurate individual survival predictions. If validated, this type of assessment could be used to guide therapy in patients with retinoblastoma.

Perspectives of using microRNA-loaded nanocarriers for epigenetic reprogramming of drug resistant colorectal cancers.

Epigenetic regulation by microRNAs (miRs) demonstrated a promising therapeutic potential of these molecules to regulate genetic activity in different cancers, including colorectal cancers (CRCs). The RNA-based therapy does not change genetic codes in tumor cells but can silence oncogenes and/or reactivate inhibited tumor suppressor genes. In many cancers, specific miRs were shown to promote or stop tumor progression. Among confirmed and powerful epigenetic regulators of colon carcinogenesis and development of resistance are onco-miRs, which include let-7, miR-21, miR-22, miR-23a, miR-27a, miR-34, miR-92, miR-96, miR-125b, miR-135b, miR-182, miR-200c, miR-203, miR-221, miR-421, miR-451, and others. Moreover, various tumor-suppressor miRs (miR-15b-5b, miR-18a, miR-20b, miR-22, miR-96, miR-139-5p, miR-145, miR-149, miR-197, miR-199b, miR-203, miR-214, miR-218, miR-320, miR-375-3p, miR-409-3p, miR-450b-5p, miR-494, miR-577, miR-874, and others) were found silenced in drug-resistant CRCs. Re-expression of tumor suppressor miR is complicated by the chemical nature of miRs that are not long-lasting compounds and require protection from the enzymatic degradation. Several recent studies explored application of miRs using nanocarrier complexes. This study critically describes the most successfully tested nanoparticle complexes used for intracellular delivery of nuclear acids and miRs, including micelles, liposomes, inorganic and polymeric NPs, dendrimers, and aptamers. Nanocarriers shield incorporated miRs and improve the agent stability in circulation. Attachment of antibodies and/or specific peptide or ligands facilitates cell-targeted miR delivery. Addressing in vivo challenges, a broad spectrum of non-toxic materials has been tested and indicated reliable advantages of lipid-based (lipoplexes) and polymer-based liposomes. Recent cutting-edge developments indicated that lipid-based complexes with multiple cargo, including several miRs, are the most effective approach to eradicate drug-resistant tumors. Focusing on CRC-specific miRs, this review provides a guidance and insights towards the most promising direction to achieve dramatic reduction in tumor growth and metastasis using miR-nanocarrier complexes.

Mitochondrial mutations and mitoepigenetics: Focus on regulation of oxidative stress-induced responses in breast cancers.

Epigenetic regulation of mitochondrial DNA (mtDNA) is an emerging and fast-developing field of research. Compared to regulation of nucler DNA, mechanisms of mtDNA epigenetic regulation (mitoepigenetics) remain less investigated. However, mitochondrial signaling directs various vital intracellular processes including aerobic respiration, apoptosis, cell proliferation and survival, nucleic acid synthesis, and oxidative stress. The later process and associated mismanagement of reactive oxygen species (ROS) cascade were associated with cancer progression. It has been demonstrated that cancer cells contain ROS/oxidative stress-mediated defects in mtDNA repair system and mitochondrial nucleoid protection. Furthermore, mtDNA is vulnerable to damage caused by somatic mutations, resulting in the dysfunction of the mitochondrial respiratory chain and energy production, which fosters further generation of ROS and promotes oncogenicity. Mitochondrial proteins are encoded by the collective mitochondrial genome that comprises both nuclear and mitochondrial genomes coupled by crosstalk. Recent reports determined the defects in the collective mitochondrial genome that are conducive to breast cancer initiation and progression. Mutational damage to mtDNA, as well as its overproliferation and deletions, were reported to alter the nuclear epigenetic landscape. Unbalanced mitoepigenetics and adverse regulation of oxidative phosphorylation (OXPHOS) can efficiently facilitate cancer cell survival. Accordingly, several mitochondria-targeting therapeutic agents (biguanides, OXPHOS inhibitors, vitamin-E analogues, and antibiotic bedaquiline) were suggested for future clinical trials in breast cancer patients. However, crosstalk mechanisms between altered mitoepigenetics and cancer-associated mtDNA mutations remain largely unclear. Hence, mtDNA mutations and epigenetic modifications could be considered as potential molecular markers for early diagnosis and targeted therapy of breast cancer. This review discusses the role of mitoepigenetic regulation in cancer cells and potential employment of mtDNA modifications as novel anti-cancer targets.

Long-Term Risk of Subsequent Malignant Neoplasms Among Childhood and Adolescent Lymphoma Survivors (1975-2013): A Population-Based Predictive Nomogram.

BACKGROUND: Studies are needed to assess risk factors pertinent to the incidence of secondary malignancies among childhood and adolescent lymphoma survivors. We aimed to identify risk factors pertinent to the incidence of secondary malignancies and subsequently establish a clinically practical predictive nomogram. METHODS: A total of 5561 patients who were diagnosed with primary lymphoma below the age of 20 years between 1975 and 2013 and survived for at least 5 years were identified. Standardized incidence ratio (SIR) and excess risk (ER) analysis were performed by sex, age, and year when primary lymphoma was diagnosed, sites and types of primary lymphoma, and therapy strategies. Univariable and multivariable logistic regression were used to identify independent risk factors for adolescent and childhood lymphoma-related secondary malignancies. Based on 5 factors (age, time from lymphoma diagnosis, gender, lymphoma type, and therapy), a nomogram for predicting the risk of a secondary malignancy for patients with childhood and adolescent primary lymphoma was established. RESULTS: Among 5561 lymphoma survivors, 424 developed a secondary malignancy. Females (SIR = 5.34, 95% CI, 4.73-5.99; ER = 50.58) exhibited a higher SIR and ER than males (SIR = 3.28, 95% CI, 2.76-3.87; ER = 15.53). Blacks were at a higher risk than Caucasians or others. Nodular lymphocyte-predominant Hodgkin lymphoma survivors exhibited typically high SIR (13.13, 95% CI, 6-24.92) and ER (54.79) among all lymphoma classifications. Lymphoma survivors who underwent radiotherapy, whether they received chemotherapy or not, had typically higher SIR and ER. Among all types of secondary malignancies, "bone and joint neoplasms" (SIR = 11.07, 95% CI, 5.52-19.81) and "soft tissue neoplasms" (SIR = 12.27, 95% CI, 7.59-18.76) presented significantly high SIR whereas "breast cancer" and "endocrine cancer" associated with higher ER. The median diagnosis age of secondary malignancies was 36 years old, and the median time interval between the diagnosis of two malignancies was 23 years. A nomogram was constructed to predict the risk of secondary malignancies in patients diagnosed with primary lymphoma before 20 years of age. After internal validation, the AUC and C-index of the nomogram are 0.804 and 0.804, respectively. CONCLUSION AND RELEVANCE: The established nomogram provides a convenient and reliable tool for predicting the risk of a secondary malignancy among childhood and adolescent lymphoma survivors, concluding significant concern for lymphoma survivors with high-risk estimates.

Development of antibody resistance in emerging mutant strains of SARS CoV-2: Impediment for COVID-19 vaccines.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a highly infectious agent associated with unprecedented morbidity and mortality. A failure to stop growth of COVID-19-linked morbidity rates is caused by SARS-CoV-2 mutations and the emergence of new highly virulent SARS-CoV-2 strains. Several acquired SARS-CoV-2 mutations reflect viral adaptations to host immune defence. Mutations in the virus Spike-protein were associated with the lowered effectiveness of current preventive therapies, including vaccines. Recent in vitro studies detected diminished neutralisation capacity of vaccine-induced antibodies, which are targeted to bind Spike receptor-binding and N-terminal domains in the emerging strains. Lower than expected inhibitory activity of antibodies was reported against viruses with E484K Spike mutation, including B.1.1.7 (UK), P.1 (Brazil), B.1.351 (South African), and new Omicron variant (B.1.1.529) with E484A mutation. The vaccine effectiveness is yet to be examined against new mutant strains of SARS-CoV-2 originating in Europe, Nigeria, Brazil, South Africa, and India. To prevent the loss of anti-viral protection in vivo, often defined as antibody resistance, it is required to target highly conserved viral sequences (including Spike protein) and enhance the potency of antibody cocktails. In this review, we assess the reported mutation-acquiring potential of coronaviruses and compare efficacies of current COVID-19 vaccines against 'parent' and 'mutant' strains of SARS-CoV-2 (Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529)).

Retrospective analysis: 5509 cases of "totally implantable venous access port systems implantation (TIVAPS) depth" assisted by digital radiography.

PURPOSE: Modern oncological treatment in breast cancer patients requires the precise delivery of chemotherapy infusion into the central venous systems without toxicity. TIVAPS is the significant method of chemotherapy delivery although certain internal or external complications associated with their placement. However, the long-term use of TIVAPS is still a concern to minimize the complications such as venous thrombosis syndrome (VTS) and cardiac defects. The aim of this study is to investigate the potential disadvantages that may be avoided by digital radiography (DR)-assisted measurement of catheter depth pertinent to TIVAPS implanted system. METHODS: Retrospective analysis related to 5509 TIVAPS recipients of 99% female breast cancer patients and 1% male blood disorder patients registered from April 2013 to November 2017 were included in the study. Patients with TIVAPS catheter tip depth into superior vena cava into upper (group A), middle (group B), and lower (group C) parts were stratified for evaluation during implantation; DR-assisted measurement of TIVAPS was performed to decipher "tip depth of catheter" and determined the relevance of tip depth to complications such as VTS and cardiac defects. RESULTS: Incidence of VTS complications were significantly higher in TIVAPS recipients of group A (82.7%) than group B (16%) and group C (0.12%) in which the "tip depth of TIVAPS was deeper" (P < 0.01). Defects in heart function are higher in group C (59.6%) than group A (15.8%) and group B (24.6%) in which the "tip depth of TIVAPS was deeper" (P < 0.01). CONCLUSION: DR-assisted measurement can more accurately determine the depth of TIVAPS catheter implantation, and avoid the incidence of related complications, and provide a better method for surgeons.

The mystery of claustral neural circuits and recent updates on its role in neurodegenerative pathology.

INTRODUCTION: The claustrum is a structure involved in formation of several cortical and subcortical neural microcircuits which may be involved in such functions as conscious sensations and rewarding behavior. The claustrum is regarded as a multi-modal information processing network. Pathology of the claustrum is seen in certain neurological disorders. To date, there are not enough comprehensive studies that contain accurate information regarding involvement of the claustrum in development of neurological disorders. OBJECTIVE: Our review aims to provide an update on claustrum anatomy, ontogenesis, cytoarchitecture, neural networks and their functional relation to the incidence of neurological diseases. MATERIALS AND METHODS: A literature review was conducted using the Google Scholar, PubMed, NCBI MedLine, and eLibrary databases. RESULTS: Despite new methods that have made it possible to study the claustrum at the molecular, genetic and epigenetic levels, its functions and connectivity are still poorly understood. The anatomical location, relatively uniform cytoarchitecture, and vast network of connections suggest a divergent role of the claustrum in integration and processing of input information and formation of coherent perceptions. Several studies have shown changes in the appearance, structure and volume of the claustrum in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), autism, schizophrenia, and depressive disorders. Taking into account the structure, ontogenesis, and functions of the claustrum, this literature review offers insight into understanding the crucial role of this structure in brain function and behavior.

MiRNAs as Noninvasive Biomarkers and Therapeutic Agents of Pituitary Adenomas.

Pituitary adenoma (PA) accounts for 10-15% of all intracranial neoplasms. Even though most pituitary adenomas are benign, it is known that almost 35% of them exhibit an aggressive clinical course, including rapid proliferative activity and invasion of neighboring tissues. MicroRNAs (miRNAs) are short single-stranded RNA molecules that can influence post-transcriptional regulation by controlling target genes. Based on research data on miRNAs over the past 20 years, more than 60% of genes encoding human proteins are regulated by miRNAs, which ultimately control basic cellular mechanisms, including cell proliferation, differentiation, and apoptosis. Dysregulation of miRNAs has been observed in a number of diseases, especially tumors like PA. A majority of miRNAs are expressed within the cells themselves. However, the circulating miRNAs can be detected in several biological fluids of the human body. The identification of circulating miRNAs as new molecular markers may increase the ability to detect a tumor, predict the course of a disease, plan to choose suitable treatment, and diagnose at the earliest signs of impending neoplastic transformation. Therapy of PAs with aggressive behavior is a complex task. When surgery and chemotherapy fail, radiotherapy becomes the treatment of choice against PAs. Therefore, the possibility of implementing circulating miRNAs as innovative diagnostic and therapeutic agents for PA is one of the main exciting ideas.

The Role of Exosomes in Stemness and Neurodegenerative Diseases-Chemoresistant-Cancer Therapeutics and Phytochemicals.

Exosomes exhibit a wide range of biological properties and functions in the living organisms. They are nanometric vehicles and used for delivering drugs, as they are biocompatible and minimally immunogenic. Exosomal secretions derived from cancer cells contribute to metastasis, immortality, angiogenesis, tissue invasion, stemness and chemo/radio-resistance. Exosome-derived microRNAs (miRNAs) and long non-coding RNAs (lnc RNAs) are involved in the pathophysiology of cancers and neurodegenerative diseases. For instance, exosomes derived from mesenchymal stromal cells, astrocytes, macrophages, and acute myeloid leukemia (AML) cells are involved in the cancer progression and stemness as they induce chemotherapeutic drug resistance in several cancer cells. This review covered the recent research advances in understanding the role of exosomes in cancer progression, metastasis, angiogenesis, stemness and drug resistance by illustrating the modulatory effects of exosomal cargo (ex. miRNA, lncRNAs, etc.) on cell signaling pathways involved in cancer progression and cancer stem cell growth and development. Recent reports have implicated exosomes even in the treatment of several cancers. For instance, exosomes-loaded with novel anti-cancer drugs such as phytochemicals, tumor-targeting proteins, anticancer peptides, nucleic acids are known to interfere with drug resistance pathways in several cancer cell lines. In addition, this review depicted the need to develop exosome-based novel diagnostic biomarkers for early detection of cancers and neurodegenerative disease. Furthermore, the role of exosomes in stroke and oxidative stress-mediated neurodegenerative diseases including Alzheimer's disease (AD), and Parkinson's disease (PD) is also discussed in this article.

Can miRNAs Be Considered as Diagnostic and Therapeutic Molecules in Ischemic Stroke Pathogenesis?-Current Status.

Ischemic stroke is one of the leading causes of death worldwide. Clinical manifestations of stroke are long-lasting and causing economic burden on the patients and society. Current therapeutic modalities to treat ischemic stroke (IS) are unsatisfactory due to the intricate pathophysiology and poor functional recovery of brain cellular compartment. MicroRNAs (miRNA) are endogenously expressed small non-coding RNA molecules, which can act as translation inhibitors and play a pivotal role in the pathophysiology associated with IS. Moreover, miRNAs may be used as potential diagnostic and therapeutic tools in clinical practice; yet, the complete role of miRNAs is enigmatic during IS. In this review, we explored the role of miRNAs in the regulation of stroke risk factors viz., arterial hypertension, metabolic disorders, and atherosclerosis. Furthermore, the role of miRNAs were reviewed during IS pathogenesis accompanied by excitotoxicity, oxidative stress, inflammation, apoptosis, angiogenesis, neurogenesis, and Alzheimer's disease. The functional role of miRNAs is a double-edged sword effect in cerebral ischemia as they could modulate pathological mechanisms associated with risk factors of IS. miRNAs pertaining to IS pathogenesis could be potential biomarkers for stroke; they could help researchers to identify a particular stroke type and enable medical professionals to evaluate the severity of brain injury. Thus, ascertaining the role of miRNAs may be useful in deciphering their diagnostic role consequently it is plausible to envisage a suitable therapeutic modality against IS.

Robotic nipple sparing mastectomy and immediate breast reconstruction: significant attempts with the latissimus dorsi muscle without island flap.

BACKGROUND: This study presents preliminary results of robot-assisted nipple-sparing immediate breast reconstruction (R-NSMIBR) with gel implant combined with latissimus dorsi muscle flap without island flap and validation of the safety and utility of this novel surgical modality. METHODS: Records pertinent to R-NSMIBR with gel implants combined with latissimus dorsi muscle flap surgery for breast reconstruction between September 2022 and May 2023 were examined. A total of 13 patients who underwent R-NSMIBR were analyzed, nine of which were performed without skin island. RESULTS: We divided the patients with and without skin islands into two groups and recorded the operation time and bleeding respectively. The mean total operative time for R-NSMIBR was 436.5±56.88 minutes and 355.75±69.68 minutes. As experience in learning increased, time required to create the operating space and position the robotic arm decreased significantly. Not creating an island of skin also saves a great deal of surgical time. Average total blood loss was 37.5±6.45 mL and 26.25±7.5 mL. No cases of nipple-areolar complex necrosis or perioperative complications or no local recurrences were reported. There were no local recurrences or deaths that occurred during a mean follow-up period of 3±1 months. CONCLUSIONS: All the patients expressed satisfaction with the aesthetic outcome following surgery. There were no significant differences between two groups. This surgical method shows promise for future promotion in the field.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.

Metformin Effects on SHIP2, AMPKs and Gut Microbiota: Recent Updates on Pharmacology.

INTRODUCTION: Metformin, a biguanide on the WHO's list of essential medicines has a long history of 50 years or more in treating hyperglycemia, and its therapeutic saga continues beyond diabetes treatment. Glucoregulatory actions are central to the physiological effects of metformin; surprisingly, the precise mechanism with which metformin regulates glucose metabolism is not thoroughly understood yet. METHOD: The main aim of this review is to explore the recent implications of metformin in hepatic gluconeogenesis, AMPKs, and SHIP2 and subsequently to elucidate the metformin action across intestine and gut microbiota. We have searched PubMed, google scholar, Medline, eMedicine, National Library of Medicine (NLM), clinicaltrials.gov (registry), and ReleMed for the implications of metformin with its updated role in AMPKs, SHIP2, and hepatic gluoconeogenesis, and gut microbiota. In this review, we have described the efficacy of metformin as a drug repurposing strategy in modulating the role of AMPKs and lysosomal-AMPKs, and controversies associated with metformin. RESULT: Research suggests that biguanide exhibits hormetic effects depending on the concentrations used (micromolar to millimolar). The primary mechanism attributed to metformin action is the inhibition of mitochondrial complex I, and subsequent reduction of cellular energy state, as observed with increased AMP or ADP ratio, thereby metformin can also activate the cellular energy sensor AMPK to inhibit hepatic gluconeogenesis. However, new mechanistic models have been proposed lately to explain the pleiotropic actions of metformin; at low doses, metformin can activate lysosomal-AMPK via the AXIN-LKB1 pathway. Conversely, in an AMPK-independent mechanism, metformin-induced elevation of AMP suppresses adenylate cyclase and glucagon-activated cAMP production to inhibit hepatic glucose output by glucagon. Metformin inhibits mitochondrial glycerophosphate dehydrogenase; mGPDH, and increases the cytosolic NADH/NAD+, affecting the availability of lactate and glycerol for gluconeogenesis. Metformin can inhibit Src homology 2 domain-containing inositol 5-phosphatase 2; SHIP2 to increase the insulin sensitivity and glucose uptake by peripheral tissues. CONCLUSION: In addition, new exciting mechanisms suggest the role of metformin in promoting beneficial gut microbiome and gut health; metformin regulates duodenal AMPK activation, incretin hormone secretion, and bile acid homeostasis to improve intestinal glucose absorption and utilization.

Updated Intrinsic Role of Phytochemicals against Glyphosate-induced Neurotoxicity: Systematic Review.

BACKGROUND: Glyphosate-based herbicide (GBH) formulations are organophosphorus pesticides implicated for agricultural use. Several epidemiological reports have reported that the occupational exposure of farmers to glyphosate can cause age-related neurodegeneration. OBJECTIVE: the objective of this study is to examine the neurotoxic effects of glyphosate and its intricate role in triggering several neurodegenerative diseases like dementia, nootropic defects, Parkinson's disease, and neurological teratogenic effects due to its negative effects on the nervous system. Furthermore, the efficacy of phytochemicals against glyphosate-induced neurotoxicity was discussed. METHODS: We have searched public databases such as NLM, Pubmed, google scholar and collected a total of 103 articles including reviews, original articles, and obtained information related to glyphosate-induced neurotoxicity and novel phytochemicals implicated to ameliorate the glyphosate-induced neurotoxicity. We performed a systematic review without comprehensive meta-analysis. RESULTS: the efficacy of several phytochemicals as a nutritional intervention against glyphosate-induced neurotoxicity including Parkinsonism was elucidated by vivid review analysis of neurobehavioral alterations from in vitro and in vivo study models. CONCLUSION: These kinds of research projects will bring awareness about the neurotoxic effects of glyphosate and the protective nutritional intervention strategies against glyphosate-induced neurotoxicity including Parkinsonism for farmers.

Breast Cancer-related Lymphedema: Recent Updates on Clinical Efficacy of Therapies and Bioengineering Approaches for a Personalized Therapy.

BACKGROUND: Post-mastectomy lymphedema is a chronic progressive disease characterized by a significant reduction in quality of life and a range of complications. AIM: To this date, no single treatment method provides pathological correction of the mechanisms associated with tissue reorganization observed in later-stage breast cancer-related lymphedema (BCRL). METHODS: To define a personalized approach to the management of patients with iatrogenic lymphedema, we performed a systematic review of literature without a comprehensive meta-analysis to outline existing molecular- genetic patterns, overview current treatment methods and their efficacy, and highlight the specific tissue-associated changes in BCRL conditions and other bio-engineering approaches to develop personalized therapy. RESULTS: Our results show that several tissue-specific and pathological molecular markers may be found, yet current research does not aim to define them. CONCLUSION: As such, currently, a strong foundation for further research into molecular-genetic changes in lymphedema tissue exists, and further research should focus on finding specific targets for personalized treatment through bio-engineering approaches.

Nitrosamines crisis in pharmaceuticals - Insights on toxicological implications, root causes and risk assessment: A systematic review.

The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

Novel Perspectives of TSLP and RXR Signaling in Corticosteroid-Resistant Asthma: Updates on TSLP Blockers.

Previous studies described that asthma patients who received corticosteroid therapy have been constrained by the corticosteroid resistance subsequently fostered to severe refractory asthma. In this review, we discussed the implications of TSLP, RXR, the role of STAT5-activating cytokines, and IL-33/NH-cell signaling pathways, and recent clinical evidence on TSLP blockers in steroid-resistant asthma. We have searched several public databases such as Pubmed, Scopus, and Relemed and obtained information pertinent to the TSLP, RXR, TSLP blockers, the STAT5-activating cytokines, and IL-33. We discussed the multiple cell signaling mechanisms underlying steroid resistance. Blocking the TSLP and other key signaling molecules like STAT5 can retrieve the sensitivity of natural helper-cells to corticosteroids. RXR derivatives treatment can modulate the activity of TSLP, which further modulates steroid resistance in severe asthmatic patients and in patients with refractory asthma. We discussed the steroid-resistance mediated by the Th2 cells and Th2-driven eosinophilia upon corticosteroid intake. Thus, this review will be beneficial for clinicians and molecular biologists to explore the inflammatory pathways associated with refractory asthma conditions and develop novel therapies against corticosteroid-resistant asthma.

SEER-Based Survival Nomogram (1998-2015) Based on 'Stage, Lymph Node Dissection, Tumor Size and Degree of Differentiation, and Therapies' for Prognosis of Primary Pulmonary Sarcoma.

Objective: Primary pulmonary sarcoma (PPS) is very rare in terms of incidence, henceforth, the clinical evidence pertinent to the prognosis of PPS is limited. The aim of this study was to construct a nomogram for evaluating the overall survival (OS) of patients diagnosed with PPS based on the stage, lymph node dissection, tumor size and degree of differentiation, and therapies. Methods: A total of 515 patients diagnosed with PPS during the period of 1998 to 2015 were obtained from the surveillance, epidemiology, and end results database and randomly segregated into 'training group' and 'validation group' with a ratio of 7:3. Regression analysis was executed for the training group to obtain the independent factors influencing prognosis of PPS patients. A nomogram was constructed as per the results obtained through multivariate Cox regression analysis subsequently validated using C index, receiver operating characteristic (ROC) curve, and calibration curves. Results: Age, tumor size, histology type, lymph node surgery, summary stage and differentiation grade were independent factors affecting the prognosis. C index was 0.775 and 0.737 for both training group, and validation group, respectively. Areas under the ROC curve of 1-year, 3-year, and 5-year OS were 87.6 (95% CI: 83.8-91.3), 90.1 (95% CI: 86.2-94.0) and 90.6 (95% CI: 85.8-95.4), respectively, in training group. Area under the curve values of 1-year, 3-year, and 5-year OS in the validation group were 83.1 (95% CI: 75.8-90.5), 82.9 (95% CI: 73.2-92.7) and 87.0 (95% CI: 75.9-98.1), respectively. Based on the nomogram, patients were segregated into low-risk group and high-risk group (degree of risk: cutoff score 193). OS of low-risk group was significantly higher when compared to high-risk group (P < .001) in the training group and validation group. Radiotherapy was a risk factor for the low-risk group and adjuvant chemotherapy has not exhibited influence on OS pertinent to low-risk group. However, adjuvant radiotherapy or chemotherapy both significantly improved the prognosis of PPS patients (P < .001) in the high-risk group. Conclusion: Constructed nomogram could have a strong predictive ability with higher accuracy for the prognosis of patients with PPS. Patients at low risk could not benefit from adjuvant radiotherapy or chemotherapy, while the prognosis clearly improved in the high-risk populations treated with either radiotherapy or chemotherapy.

Robot-assisted nipple-sparing mastectomy and immediate breast reconstruction with gel implant and latissimus dorsi muscle flap: Our initial experience.

BACKGROUND: This study reports the preliminary results of da Vinci robot XI robot-assisted nipple-sparing mastectomy immediate breast reconstruction (R-NSMIBR) with gel implant and latissimus dorsi muscle flap. METHODS: A total of 15 patients who underwent R-NSMIBR with gel implant and latissimus dorsi muscle flap surgery for breast cancer between September 2022 and November 2022 were evaluated. RESULTS: Mean total operative time for R-NSMIBR was 361.9 ± 77.0 min. As the learning curve increased, the robot arm docking time decreased rapidly from the initial 25-10 min. Average total blood loss was 27.8 ± 10.7 mL and posterior surgical margin positivity rate was 0%. Perioperative complications and local recurrences or deaths were not observed at a mean follow-up of 3 ± 1 month 15 patients were satisfied with postoperative aesthetic results. CONCLUSIONS: R-NSMIBR with a gel implant and latissimus dorsi muscle flap could be a new therapeutic option for breast reconstruction.