Pan-immune-inflammation value as a prognostic biomarker for colon cancer and its variation by primary tumor location.

BACKGROUND: A growing body of research indicates significant differences between left-sided colon cancers (LCC) and right-sided colon cancers (RCC). Pan-immune-inflammation value (PIV) is a systemic immune response marker that can predict the prognosis of patients with colon cancer. However, the specific distinction between PIV of LCC and RCC remains unclear. AIM: To investigate the prognostic and clinical significance of PIV in LCC and RCC patients. METHODS: This multicenter retrospective cohort study included 1510 patients with colon cancer, comprising 801 with LCC and 709 with RCC. We used generalized lifting regression analysis to evaluate the relative impact of PIV on disease-free survival (DFS) in these patients. Kaplan-Meier analysis, as well as univariate and multivariate analyses, were used to examine the risk factors for DFS. The correlation between PIV and the clinical characteristics was statistically analyzed in these patients. RESULTS: A total of 1510 patients {872 female patients (58%); median age 63 years [interquartile ranges (IQR): 54-71]; patients with LCC 801 (53%); median follow-up 44.17 months (IQR 29.67-62.32)} were identified. PIV was significantly higher in patients with RCC [median (IQR): 214.34 (121.78-386.72) vs 175.87 (111.92-286.84), P < 0.001]. After propensity score matching, no difference in PIV was observed between patients with LCC and RCC [median (IQR): 182.42 (111.88-297.65) vs 189.45 (109.44-316.02); P = 0.987]. PIV thresholds for DFS were 227.84 in LCC and 145.99 in RCC. High PIV (> 227.84) was associated with worse DFS in LCC [PIV-high: Adjusted hazard ratio (aHR) = 2.39; 95% confidence interval: 1.70-3.38; P < 0.001] but not in RCC (PIV-high: aHR = 0.72; 95% confidence interval: 0.48-1.08; P = 0.114). CONCLUSION: These findings suggest that PIV may predict recurrence in patients with LCC but not RCC, underscoring the importance of tumor location when using PIV as a colon cancer biomarker.

Posterior Hip Pericapsular Block (PHPB) with pericapsular nerve group (PENG) block for hip fracture: a case series.

BACKGROUND: Pain after total hip arthroplasty (THA) for femoral neck fracture (FNF) can be severe, potentially leading to serious complications. PENG block has become an optional local analgesic strategy in hip fracture surgery, but it cannot provide effective pain relief for the posterior capsule of the hip joint. Therefore, we modified the traditional sacral plexus nerve block and named it Posterior Hip Pericapsule Block (PHPB) to complement the blockade of the relevant nerves innervating the posterior hip capsule region. Thereby, we detail the analgesic effect of PHPB combined with PENG block on five hip fracture patients and the effect on their hip motor function. METHODS: This case series was conducted from December 2023 to February 2024. We performed ultrasound-guided PHPB combined with PENG block on five patients with hip fractures. Numerical Rating Scale (NRS) pain scores at rest and maximum NRS pain scores during limb movement of the five patients were recorded within 48 h after surgery. Their hip flexion, abduction, adduction, keen flexion and quadriceps muscle strength were also recorded. Serious postoperative complications, including wound infection, hematoma formation, or nerve injury, were recorded. RESULTS: They experienced effective pain control within 48 h postoperatively, with NRS pain scores at rest decreasing from 3.0 (3.0, 4.5) to 0.0 (0.0, 1.0) and maximum NRS pain scores during limb movement from 8.0 (7.5, 8.5) to 1.0 (0.5, 2.0). They can autonomously perform hip flexion, abduction, adduction, and knee flexion within 48 h postoperatively without any signs of movement disorders or quadriceps muscle weakness. No severe postoperative complications, such as wound infections, hematoma formation or nerve damage, were observed in any of the patients. CONCLUSIONS: Ultrasound-guided PENG block combined with PHPB provided effective analgesia for hip fracture patients in the perioperative period. It maintained hip joint motor function and quadriceps muscle strength within 24 h after THA.

Perioperative systemic and prophylactic intraperitoneal chemotherapy for type 4/large type 3 gastric cancer: DRAGON-10.

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events.Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

Gastric cancer (GC), specifically the large type 3 and type 4 kinds, is a serious health condition that often leads to a very poor chance of survival. This is mainly because these types of cancer easily spread to the lining of the abdomen, a process known as peritoneal dissemination. One way to tackle this issue is through a treatment known as intraperitoneal chemotherapy, which directly targets the abdominal lining to kill cancer cells. In our study, 37 resectable large type 3 and type 4 GC patients will receive a combination of chemotherapy drugs before undergoing surgery to remove the cancer. After surgery, they will receive additional treatment that combines chemotherapy into the abdomen with standard chemotherapy. The main goal of our study is to see if this treatment approach can reduce the chance of cancer returning to the abdominal lining within 3 years. We are also looking at how long patients remain free from cancer, their overall survival after 3 years, and any side effects they may experience from the treatment. This study aims to provide a clearer understanding of how effective this combined treatment is for patients with these aggressive types of GC, with the hope of improving their chances of survival and quality of life.

Neuroprotective effects of all-trans-retinoic acid are mediated via downregulation of TLR4/NF-κB signaling in a rat model of middle cerebral artery occlusion.

OBJECTIVES: To determine the effects of all-trans-retinoic acid (ATRA) on the post-stroke inflammatory response and elucidate the underlying molecular mechanisms. METHODS: This animal experiment was conducted at Central Laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China during 2020-2022. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h, and treated with ATRA at 2 and 24 h after reperfusion. Neurological deficit scores on behavioral tests, and cerebral infarct volume, microglial polarization, and the expression levels of inflammatory cytokines and proteins associated with TLR4/NF-κB signaling were assessed. RESULTS: The ATRA administration reduced cerebral infarct volume and ameliorated neurological deficit scores in MCAO rats. Additionally, ATRA relieved cerebral edema and downregulated the secretion of proinflammatory cytokines after stroke. Finally, ATRA attenuated the polarization of the microglia toward the M1 phenotype and promoted the activation of the beneficial M2 phenotype; the underlying mechanism potentially involved the suppression of the TLR4/NF-κB signaling pathway. CONCLUSION: The ATRA treatment promoted functional recovery in an experimental model of ischemic stroke by attenuating neural inflammation. ATRA potentially modulated microglia-mediated neuroinflammation via the downregulation of the TLR4/NF-κB signaling pathway, which makes it a candidate treatment for post-stroke neuroinflammation.

Therapeutic potential of archaeal unfoldase PANet and the gateless T20S proteasome in P23H rhodopsin retinitis pigmentosa mice.

Neurodegenerative diseases are characterized by the presence of misfolded and aggregated proteins which are thought to contribute to the development of the disease. In one form of inherited blinding disease, retinitis pigmentosa, a P23H mutation in the light-sensing receptor, rhodopsin causes rhodopsin misfolding resulting in complete vision loss. We investigated whether a xenogeneic protein-unfolding ATPase (unfoldase) from thermophilic Archaea, termed PANet, could counteract the proteotoxicity of P23H rhodopsin. We found that PANet increased the number of surviving photoreceptors in P23H rhodopsin mice and recognized rhodopsin as a substate in vitro. This data supports the feasibility and efficacy of using a xenogeneic unfoldase as a therapeutic approach in mouse models of human neurodegenerative diseases. We also showed that an archaeal proteasome, called the T20S can degrade rhodopsin in vitro and demonstrated that it is feasible and safe to express gateless T20S proteasomes in vivo in mouse rod photoreceptors. Expression of archaeal proteasomes may be an effective therapeutic approach to stimulate protein degradation in retinopathies and neurodegenerative diseases with protein-misfolding etiology.

Lymph node metastasis diagnosis of postoperative OSCC patients by analyzing extracellular vesicles in drainage fluid based on microfluidic isolation.

Lymph node metastasis (LNM) is a typical marker in oral squamous cell carcinoma (OSCC) indicating poor prognosis. Pathological examination by artificial image acquisition and analysis, as the main diagnostic method for LNM, often takes a week or longer which may cause great anxiety of the patient and also retard timely treatment. However, there are few efficient fast LNM diagnosis methods in clinical applications currently. Our previous study profiled the proteomics of extracellular vesicles (EVs) derived from postoperative drainage fluid (PDF) and showed the potential of detecting specific EVs that expressed aspartate ß-hydroxylase (ASPH) for LNM diagnosis in OSCC patients. Considering that the analysis of ASPH+ PDF-EVs is challenging due to their low abundance (counting less than 10% of total EVs in PDF) and the complex EV isolation process of ultra-centrifugation, we developed a facile platform containing two microfluidic chips filled with antibody-modified microbeads to isolate ASPH+ PDF-EVs, with both the capture and retrieval rate reaching around 90%. Clinical sample analysis based on our method revealed that a mean of 6 × 106 /mL ASPH+ PDF-EVs could be isolated from LNM+ OSCC patients compared to 2.5 × 106 /mL in LNM- OSCC ones. When combined with enzyme-linked immunosorbent assay (ELISA) technique that was commonly used in clinical laboratories in hospitals, this microfluidic platform could precisely distinguish postoperative OSCC patients with LNM or not in several hours, which were validated by a double-blind test containing 6 OSCC patients. We believe this strategy has promise for early diagnosis of LNM in postoperative OSCC patients and finally helps guiding timely and reasonable treatment in clinic.

Selection of Reference Genes of Flower Development in Ludisia discolor.

Background: RT-qPCR is a powerful strategy for recognizing the most appropriate reference genes, which can successfully minimize experimental mistakes through accurate normalization. Ludisia discolor, recognized for its ornamental value, features little, distinctive blossoms with twisted lips and gynostemium showing chiral asymmetry, together with striking blood-red fallen leaves periodically marked with golden blood vessels. Methods and Results: To ensure the accuracy of qRT-PCR, selecting appropriate reference genes for quantifying target gene expression levels is essential. This study aims to identify stable reference genes during the development of L. discolor. In this study, the entire floral buds, including the lips and gynostemium from different development stages, were taken as materials. Based upon the transcriptome information of L. discolor, nine housekeeping genes, ACT, HIS, EF1-α1, EF1-α2, PP2A, UBQ1, UBQ2, UBQ3, and TUB, were selected in this research study as prospect interior referral genes. The expression of these nine genes were found by RT-qPCR and afterwards comprehensively examined by four software options: geNorm, NormFinder, BestKeeper, and ΔCt. The outcomes of the analysis showed that ACT was the most steady gene, which could be the most effective inner referral gene for the expression evaluation of flower advancement in L. discolor. Conclusions: The results of this study will contribute to the molecular biology research of flower development in L. discolor and closely related species.

POCT Detection of Pseudomonas aeruginosa by PGM and Application of Preventing Nosocomial Infection of Bronchoscopy.

Background: The primary pathogen responsible for bronchoscope contamination is Pseudomonas aeruginosa. Conventional techniques for bronchoscopy disinfection and pathogen identification methods are characterized by time-consuming and operation complexly. The objective of this research is to establish a prompt and precise method for the identification of Pseudomonas aeruginosa, with the ultimate goal of mitigating the risk of nosocomial infections linked to this pathogen. Methods: The magnetic nanoparticles (MNPs) were synthesized in a single step, followed by the optimization of the coating process with antibodies and invertase to produce the bifunctionalized IMIc. Monoclonal antibodies were immobilized on microplates for the specific capture and enrichment of Pseudomonas aeruginosa. Upon the presence of Pseudomonas aeruginosa, the monoclonal antibodies, the test sample, and the IMIc formed sandwich structures. The subsequent addition of a sucrose solution allowed for the detection of glucose produced through invertase hydrolysis by a personal glucose meter, enabling quantitative assessment of Pseudomonas aeruginosa concentration. Results: TEM image demonstrates that the MNPs exhibit a consistent spherical shape. NTA determined that the grain diameter of magnetic nanoparticles was 200 nm. FTIR spectrum revealed the successful modification of two carboxyl groups on the MNPs. The optimization of the incubation pH of the microplate-coated antibody was 7. The optimization of the incubation time of the microplate-coated antibody was 2 h. The optimization of the ligation pH for the polyclonal antibody was 5. Reaction times of polyclonal antibodies linked to magnetic beads was 1 h. The pH of invertase linked by magnetic beads was 4. Conclusion: This article presents a novel qualitative and quantitative immunoassay for point-of-care monitoring of P. aeruginosa utilizing PGM as a readout. The PGM represents a convenient and accurate quantitative detection method suitable for potential clinical diagnostic applications.

Functional characterization of prenyltransferases involved in de novo synthesis of isoprenoids in the leaf beetle Monolepta hieroglyphica.

Prenyltransferases play a pivotal role in the isoprenoid biosynthesis and transfer in insects. In the current study, two classes of prenyltransferases (MhieFPPS1 and MhieFPPS2, MhiePFT-ß and MhiePF/GGT-α) were identified in the leaf beetle, Monolepta hieroglyphica. Phylogenetic analysis revealed that MhieFPPS1, MhieFPPS2, MhiePFT-ß and MhiePF/GGT-α were clustered in one clade with homologous in insects. Moreover, MhieFPPS2 lacked one aspartate-rich motif SARM. Molecular docking and kinetic analysis indicated that the (E)-GPP displayed higher affinity with MhieFPPS1 compared to DMAPP within the binding pocket containing metal binding sites (MG). The other class of prenyltransferases (MhiePFT-ß and MhiePF/GGT-α) lack the aspartate-rich motif. Docking results indicated that binding site of MhiePFT-ß involved divalent metal ions (Zn) and bound farnesyl or geranylgeranyl. In vitro, only recombiant MhieFPPS1 could catalyze the formation of (E)-farnesol against different combination of substrates, including IPP/DMAPP and IPP/(E)-GPP, highlighting the importance of SARM for enzyme activities. Kinetic analysis further indicated that MhiePFT-ß operated via Zn2+-dependent substrate binding, while MhiePF/GGT-α stabilized the ß-subunit during catalytic reaction. These findings contribute to a valuable insight in to understanding of the mechanisms involved in the biosynthesis and delivery of isoprenoid products in beetles.

Antioxidant Carbon Dots Nanozymes Alleviate Stress-induced Depression by Modulating Gut Microbiota.

Depression is a debilitating mental illness that severely threatens millions of individuals and public health. Because of the multifactorial etiologies, there is currently no cure for depression; thus, it is urgently imperative to find alternative antidepressants and strategies. Growing evidence underscores the prominent role of oxidative stress as key pathological hallmarks of depression, making oxidative stress a potential therapeutic target. In this study, we report a N-doped carbon dot nanozyme (CDzyme) with excellent antioxidant capacity for treating depression by remodeling redox homeostasis and gut microbiota. The CDzymes prepared via microwave-assisted fast polymerization of histidine and glucose exhibit superior biocompatibility. Benefiting from the unique structure, CDzymes can provide abundant electrons, hydrogen atoms, and protons for reducing reactions, as well as catalytic sites to mimic redox enzymes. These mechanisms collaborating endow CDzymes with broad-spectrum antioxidant capacity to scavenge reactive oxygen and nitrogen species (•OH, O2-•, H2O2, ONOO-), and oxygen/nitrogen centered free radicals. A depression animal model was established by chronic unpredictable mild stress (CUMS) to evaluate the therapeutic efficacy of CDzymes from the behavioral, physiological, and biochemical index and intestinal flora assessments. CDzymes can remarkably improve depression-like behaviors and key neurotransmitters produced in hippocampus tissues and restore the gut microbiota compositions and the amino acid metabolic functions, proving the potential in treating depression through the intestinal-brain axis system. This study will facilitate the development of intestinal flora dysbiosis nanomedicines and treatment strategies for depression and other oxidative stress related multifactorial diseases.

Parrondo's paradox reveals counterintuitive wins in biology and decision making in society.

Parrondo's paradox refers to the paradoxical phenomenon of combining two losing strategies in a certain manner to obtain a winning outcome. It has been applied to uncover unexpected outcomes across various disciplines, particularly at different spatiotemporal scales within ecosystems. In this article, we provide a comprehensive review of recent developments in Parrondo's paradox within the interdisciplinary realm of the physics of life, focusing on its significant applications across biology and the broader life sciences. Specifically, we examine its relevance from genetic pathways and phenotypic regulation, to intercellular interaction within multicellular organisms, and finally to the competition between populations and species in ecosystems. This phenomenon, spanning multiple biological domains and scales, enhances our understanding of the unified characteristics of life and reveals that adaptability in a drastically changing environment, rather than the inherent excellence of a trait, underpins survival in the process of evolution. We conclude by summarizing our findings and discussing future research directions that hold promise for advancing the field.

A Gene Cluster of Mitochondrial Complexes Contributes to the Cognitive Decline of COVID-19 Infection.

"Brain fog," a persistent cognitive impairment syndrome, stands out as a significant neurological aftermath of coronavirus disease 2019 (COVID-19). Yet, the underlying mechanisms by which COVID-19 induces cognitive deficits remain elusive. In our study, we observed an upregulation in the expression of genes linked to the inflammatory response and oxidative stress, whereas genes associated with cognitive function were downregulated in the brains of patients infected with COVID-19. Through single-nucleus RNA sequencing (snRNA-seq) analysis, we found that COVID-19 infection triggers the immune responses in microglia and astrocytes and exacerbates oxidative stress in oligodendrocytes, oligodendrocyte progenitors (OPCs), and neurons. Further investigations revealed that COVID-19 infection elevates LUC7L2 expression, which inhibits mitochondrial oxidative phosphorylation (OXPHOS) and suppresses the expression of mitochondrial complex genes such as MT-ND1, MT-ND2, MT-ND3, MT-ND4L, MT-CYB, MT-CO3, and MT-ATP6. A holistic approach to protect mitochondrial complex function, rather than targeting a single molecular, should be an effective therapeutic strategy to prevent and treat the long-term consequences of "long COVID."

Deep brain stimulation and pallidotomy in primary Meige syndrome: a prospective cohort study.

BACKGROUND: Primary Meige syndrome (PMS) is a rare form of dystonia, and comparative analysis of globus pallidus internal deep brain stimulation (GPi-DBS), subthalamic nucleus deep brain stimulation (STN-DBS), and pallidotomy has been lacking. This study aims to compare the efficacy, safety, and psychiatric features of GPi-DBS, STN-DBS, and pallidotomy in patients with PMS. METHODS: This prospective cohort study was divided into three groups: GPi-DBS, STN-DBS, and pallidotomy. Clinical assessments, including motor and non-motor domains, were evaluated at baseline and at 1 year and 3 years after neurostimulation/surgery. RESULTS: Ninety-eight patients were recruited: 46 patients received GPi-DBS, 34 received STN-DBS, and 18 underwent pallidotomy. In the GPi-DBS group, the movement score of the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) improved from a mean (SE) of 13.8 (1.0) before surgery to 5.0 (0.7) (95% CI, -10.5 to -7.1; P < 0.001) at 3 years. Similarly, in the STN-DBS group, the mean (SE) score improved from 13.2 (0.8) to 3.5 (0.5) (95% CI, -10.3 to -8.1; P < 0.001) at 3 years, and in the pallidotomy group, it improved from 14.9 (1.3) to 6.0 (1.1) (95% CI, -11.3 to -6.5; P < 0.001) at 3 years. They were comparable therapeutic approaches for PMS that can improve motor function and quality of life without non-motor side effects. CONCLUSIONS: DBS and pallidotomy are safe and effective treatments for PMS, and an in-depth exploration of non-motor symptoms may be a new entry point for gaining a comprehensive understanding of the pathophysiology.

The clinical outcome of minor changes in serum creatinine for patients after curative gastrectomy: a prospective study.

Introduction: Patients with renal insufficiency are more prone to postoperative complications (PCs). Studies have shown that minor changes in serum creatinine (SCr), immediately post-surgery, can aid in assessing patients' renal function. This study aimed to explore the relationship between the changes in SCr and PCs in patients with gastric cancer (GC). Materials and methods: We prospectively collected data regarding the SCr of 530 GC patients, within 2 weeks before surgery and within 24 hours after surgery in our hospital (2014-2016). The patients were divided into three groups according to the level of SCr change after surgery: reduced (<10%), normal (10%), and elevated (>10%) creatinine groups. Univariate and multivariate logistic analysis were performed to evaluate its correlation with short-term PCs in the patients. The R language was used to construct a nomogram. Results: 83, 217, and 230 patients were assigned to the elevated, reduced, and normal SCr groups, respectively. Multivariate analysis showed that the reduced and elevated SCr groups were independently associated with the occurrence of PCs and severe postoperative complications (SPCs), respectively. Additionally, postsurgical SCr change, age, hypoalbuminemia, total gastrectomy, combined resection, and laparoscopy, were independently related to PCs. Combining the above influential factors, the predictive model can distinguish patients with PCs more reliably (c-index is 0.715). Conclusion: Post-surgery, reduced SCr is a protective factor for PCs, while elevated serum creatinine is an independent risk factor for SPCs. Our nomogram can identify GC patients with high risks of PCs.

Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.

Human ABC transporters ABCD1-3 are all localized on the peroxisomal membrane and participate in the ß-oxidation of fatty acyl-CoAs, but they differ from each other in substrate specificity. The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly. Here we report two cryogenic electron microscopy (cryo-EM) structures of ABCD3 bound to phytanoyl-CoA and ATP at resolutions of 2.9 Å and 3.2 Å, respectively. A pair of phytanoyl-CoA molecules were observed in ABCD3, each binding to one transmembrane domain (TMD), which is distinct from our previously reported structure of ABCD1, where each fatty acyl-CoA molecule strongly crosslinks two TMDs. Upon ATP binding, ABCD3 exhibits a conformation that is open towards the peroxisomal matrix, leaving two extra densities corresponding to two CoA molecules deeply embedded in the translocation cavity. Structural analysis combined with substrate-stimulated ATPase activity assays indicated that the present structures might represent two states of ABCD3 in the transport cycle. These findings advance our understanding of fatty acid oxidation and the molecular pathology of related diseases.

Phototriggered Self-Catalyzed Phosphorylation of 3,4-Dihydroquinoxalin-2(1H)-ones with Diarylphosphine Oxides in EtOH.

A highly effective external photocatalyst- and additive-free method for the phosphorylation of 3,4-dihydroquinoxalin-2(1H)-ones to produce phosphorylated dihydroquinoxalin-2(1H)-ones has been reported. A wide variety of phosphorylated products were formed in good to excellent yields. Preliminary mechanistic studies reveal that the phosphorylation process involves an EnT process, a SET process, a HAT process, and a deprotonation process.

Wastewaters Coproduced with Shale Gas Drive Slight Regional Salinization of Groundwater.

While unconventional oil and gas (UOG) development is changing the world economy, processes that are used during UOG development such as high-volume hydraulic fracturing ("fracking") have been linked with water contamination. Water quality risks include leaks of gas and salty fluids (brines) that are coproduced at wellpads. Identifying the cause of contamination is difficult, however, because UOG wells are often colocated with other contaminant sources. We investigated the world's largest shale gas play with publicly accessible groundwater data (Marcellus Shale in Pennsylvania, U.S.A. with ∼29,000 analyses) and discovered that concentrations of brine-associated barium ([Ba]) and strontium ([Sr]) show small regional increases within 1 km of UOG development. Higher concentrations in groundwaters are associated with greater proximity to and density of UOG wells. Concentration increases are even larger when considering associations with the locations of (i) spill-related violations and (ii) some wastewater impoundments. These statistically significant relationships persist even after correcting for other natural and anthropogenic sources of salts. The most likely explanation is that UOG development slightly increases salt concentrations in regional groundwaters not because of fracking but because of the ubiquity of wastewater management issues. These results emphasize the need for stringent wastewater management practices across oil and gas operations.

Neo-adjuvant radiation and intratumoral immunotherapy followed by surgery-NARIS trial for extremity soft tissue sarcoma.

Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms.Clinical Trial Registration: ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov).

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Unravelling oncosis: morphological and molecular insights into a unique cell death pathway.

Programmed cell death (PCD) is a fundamental biological process for maintaining cellular equilibrium and regulating development, health, and disease across all living organisms. Among the various types of PCD, apoptosis plays a pivotal role in numerous diseases, notably cancer. Cancer cells frequently develop mechanisms to evade apoptosis, increasing resistance to standard chemotherapy treatments. This resistance has prompted extensive research into alternative mechanisms of programmed cell death. One such pathway is oncosis, characterized by significant energy consumption, cell swelling, dilation of the endoplasmic reticulum, mitochondrial swelling, and nuclear chromatin aggregation. Recent research suggests that oncosis can impact conditions such as chemotherapeutic cardiotoxicity, myocardial ischemic injury, stroke, and cancer, mediated by specific oncosis-related proteins. In this review, we provide a detailed examination of the morphological and molecular features of oncosis and discuss various natural or small molecule compounds that can induce this type of cell death. Additionally, we summarize the current understanding of the molecular mechanisms underlying oncosis and its role in both normal physiology and pathological conditions. These insights aim to illuminate future research directions and propose innovative strategies for leveraging oncosis as a therapeutic tool against human diseases and cancer resistance.

Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies.

HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. Here, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%), had a poor response to current anti-HER2 dual-targeted therapies and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment.