Plasma Lipidomic Profiling Identifies Elevated Triglycerides as Potential Risk Factor in Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment, often necessitating dose reduction (DR) or chemotherapy discontinuation (CD). Studies on peripheral neuropathy related to chemotherapy, obesity, and diabetes have implicated lipid metabolism. This study examined the association between circulating lipids and CIPN. METHODS: Lipidomic analysis was performed on plasma samples from 137 patients receiving taxane-based treatment. CIPN was graded using Total Neuropathy Score-clinical version (TNSc) and patient-reported outcome measure European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (EORTC-QLQ-CIPN20). RESULTS: A significant proportion of elevated baseline lipids were associated with high-grade CIPN defined by TNSc and EORTC-QLQ-CIPN20 including triacylglycerols (TGs). Multivariable Cox regression on lipid species, adjusting for BMI, age, and diabetes, showed several elevated baseline TG associated with shorter time to DR/CD. Latent class analysis identified two baseline lipid profiles with differences in risk of CIPN (hazard ratio, 2.80 [95% CI, 1.50 to 5.23]; P = .0013). The higher risk lipid profile had several elevated TG species and was independently associated with DR/CD when modeled with other clinical factors (diabetes, age, BMI, or prior numbness/tingling). CONCLUSION: Elevated baseline plasma TG is associated with an increased risk of CIPN development and warrants further validation in other cohorts. Ultimately, this may enable therapeutic intervention.

CuPc-Fe@BSA nanocomposite: Intracellular acid-sensitive aggregation for enhanced sonodynamic and chemo-therapy.

Due to their rigid π-conjugated macrocyclic structure, organic sonosensitizers face significant aggregation in physiological conditions, hindering the production of reactive oxygen species (ROS). An acid-sensitive nanoassembly was developed to address this issue and enhance sonodynamic therapy (SDT) and emission. Initially, copper phthalocyanine (CuPc) was activated using a H2SO4-assisted hydrothermal method to introduce multiple functional groups (-COOH, -OH, and -SO3H), disrupting strong π-π stacking and promoting ROS generation and emission. Subsequently, negatively charged CuPc-SO4 was incorporated into bovine serum albumin (BSA) to form CuPc-Fe@BSA nanoparticles (10 nm) with Fe3+ ions serving as linkers. In acidic conditions, protonation of CuPc-SO4 and BSA weakened the interactions, leading to Fe3+ release and nanostructure dissociation. Protonated CuPc-SO4 tended to self-aggregate into nanorods. This acidity-sensitive aggregation is vital for achieving specific accumulation within the tumor microenvironment (TME), thereby enhancing retention and SDT efficacy. Prior to this, the nanocomposites demonstrated cycling stability under neutral conditions. Additionally, the released Fe ions exhibited mimicry of glutathione peroxidase and peroxidase activity for chemotherapy (CDT). The synergistic effect of SDT and CDT increased intracellular oxidative stress, causing mitochondrial injury and ferroptosis. Furthermore, the combined therapy induced immunogenic cell death (ICD), effectively activating anticancer immune responses and suppressing metastasis and recurrence.

Safety and efficacy of indocyanine green fluorescence imaging-guided laparoscopic para-aortic lymphadenectomy for left-sided colorectal cancer:A preliminary case-matched study.

AIM: This study is aimed to explore the safety and feasibility of indocyanine green (ICG) fluorescence imaging guidance in laparoscopic para-aortic lymph node (PALN) dissection for left-sided colorectal cancer (CRC) patients with clinically suspected PALN metastasis. METHOD: A total of 151 patients who underwent primary tumor resection and laparoscopic PALN dissection for left-sided CRC were included, with 20 patients in the ICG group and 131 patients in the non-ICG group. The surgical outcomes, postoperative complications, and pathological results, such as the number of harvested and metastatic lymph nodes were compared between groups after propensity score matching. RESULTS: Following propensity score matching, the ICG group had 20 patients, and the non-ICG group had 53 patients, and the two groups were similar in baseline characteristics. No significant differences were observed in overall intraoperative and postoperative complications between groups, except for chylous leakage, where the ICG group had a longer time to a normal diet. The number of harvested pericolic/perirectal and intermediate lymph nodes were comparable between the two groups, while the ICG group had a significantly higher number of total harvested lymph nodes (39 [14-78] vs. 29 [11-70], P = 0.001), inferior mesenteric artery lymph nodes (IMALN, 6 [0-17] vs. 3 [0-11], P = 0.006), and PALNs (9 [3-29] vs. 5 [1-37], P = 0.001). CONCLUSION: ICG fluorescence imaging could increase the retrieval of IMALN, PALN, and total lymph nodes, and potentially improve the completeness of laparoscopic PALN dissection in patients with left-sided CRC.

An Intelligent and Soluble Microneedle Composed of Bi/BiVO4 Schottky Heterojunction for Tumor Ct Imaging and Starvation/Gas Therapy-Promoted Synergistic Cancer Treatment.

Phototherapy and sonodynamic therapy (SDT) are widely used for the synergistic treatment of tumors and have received considerable attention. However, an inappropriate tumor microenvironment, including pH, H2O2, oxygen, and glutathione levels, can reduce the therapeutic effects of synergistic phototherapy and SDT. Here, a novel Bi-based soluble microneedle (MN) is designed for the CT imaging of breast tumors and starvation therapy/gas therapy-enhanced phototherapy/SDT. The optimized Bi/BiVO4 Schottky heterojunction serves as the tip of the MN, which not only has excellent photothermal conversion ability and CT contrast properties, but its heterojunction can also avoid the rapid combination of electrons and hole pairs, thereby enhancing the photodynamic/sonodynamic effects. A degradable MN with excellent mechanical properties is fabricated by optimizing the ratios of poly(vinyl alcohol), poly(vinyl pyrrolidone), and sodium hyaluronate. Glucose oxidase (GOx) and diallyl trisulfide are loaded into the MN to achieve tumor starvation and gas therapy, respectively; And the controlled release of GOx and H2S can be achieved under ultrasound or near-infrared laser irradiation. The in vitro and in vivo results demonstrate that this multifunctional MN can achieve high therapeutic efficacy through starvation therapy/gas therapy-enhanced phototherapy/SDT. The designed multifunctional MN provides a prospective approach for synergistic phototherapy and SDT.

Interrater Agreement of CT Grading of Blunt Splenic Injuries: Does the AAST Grading Need to Be Reimagined?

Introduction: The Revised Organ Injury Scale (OIS) of the American Association for Surgery of Trauma (AAST) is the most widely accepted classification of splenic trauma. The objective of this study was to evaluate inter-rater agreement for CT grading of blunt splenic injuries. Methods: CT scans in adult patients with splenic injuries at a level 1 trauma centre were independently graded by 5 fellowship trained abdominal radiologists using the AAST OIS for splenic injuries - 2018 revision. The inter-rater agreement for AAST CT injury score, as well as low-grade (IIII) versus high-grade (IV-V) splenic injury was assessed. Disagreement in two key clinical scenarios (no injury versus injury, and high versus low grade) were qualitatively reviewed to identify possible sources of disagreement. Results: A total of 610 examinations were included. The inter-rater absolute agreement was low (Fleiss kappa statistic 0.38, P < 0.001), but improved when comparing agreement between low and high grade injuries (Fleiss kappa statistic of 0.77, P < .001). There were 34 cases (5.6%) of minimum two-rater disagreement about no injury vs injury (AAST grade ≥ I). There were 46 cases (7.5%) of minimum two-rater disagreement of low grade (AAST grade I-III) versus high grade (AAST grade IV-V) injuries. Likely sources of disagreement were interpretation of clefts versus lacerations, peri-splenic fluid versus subcapsular hematoma, application of adding multiple low grade injuries to higher grade injuries, and identification of subtle vascular injuries. Conclusion: There is low absolute agreement in grading of splenic injuries using the existing AAST OIS for splenic injuries.

PCPro: a clinically accessible, circulating lipid biomarker signature for poor-prognosis metastatic prostate cancer.

BACKGROUND: Using comprehensive plasma lipidomic profiling from men with metastatic castration-resistant prostate cancer (mCRPC), we have previously identified a poor-prognostic lipid profile associated with shorter overall survival (OS). In order to translate this biomarker into the clinic, these men must be identifiable via a clinically accessible, regulatory-compliant assay. METHODS: A single regulatory-compliant liquid chromatography-mass spectrometry assay of candidate lipids was developed and tested on a mCRPC Discovery cohort of 105 men. Various risk-score Cox regression prognostic models of OS were built using the Discovery cohort. The model with the highest concordance index (PCPro) was chosen for validation and tested on an independent Validation cohort of 183 men. RESULTS: PCPro, the lipid biomarker, contains Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), triglycerides and total cholesterol. Within the Discovery and Validation cohorts, men who were PCPro positive had significantly shorter OS compared to those who were PCPro negative (Discovery: median OS 12.0 months vs 24.2 months, hazard ratio (HR) 3.75 [95% confidence interval (CI) 2.29-6.15], p < 0.001, Validation: median OS 13.0 months vs 25.7 months, HR = 2.13 [95% CI 1.46-3.12], p < 0.001). CONCLUSIONS: We have developed PCPro, a lipid biomarker assay capable of prospectively identifying men with mCRPC with a poor prognosis. Prospective clinical trials are required to determine if men who are PCPro positive will benefit from therapeutic agents targeting lipid metabolism.

Porous Molybdenum Nitride Nanosphere as Carrier-Free and Efficient Nitric Oxide Donor for Synergistic Nitric Oxide and Chemo/Sonodynamic Therapy.

Given its abundant physiological functions, nitric oxide (NO) has attracted much attention as a cancer therapy. The sensitive release and great supply capacity are significant indicators of NO donors and their performance. Here, a transition metal nitride (TMN) MoN@PEG is adopted as an efficient NO donor. The release process starts with H+-triggered denitrogen owing to the high electronegativity of the N atom and weak Mo-N bond. Then, these active NHx are oxidized by O2 and other reactive oxygen species (ROS) to form NO, endowing specific release to the tumor microenvironment (TME). With a porous nanosphere structure (80 nm), MoN@PEG does not require an extra carrier for NO delivery, contributing to ultrahigh atomic utilization for outstanding release ability (94.1 ± 5.6 µM). In addition, it can also serve as a peroxidase and sonosensitizer for anticancer treatment. To further improve the charge separation, MoN-Pt@PEG was prepared to enhance the sonodynamic therapy (SDT) effect. Accordingly, ultrasound (US) further promotes NO generation due to more ROS generation, facilitating in situ peroxynitrite (·ONOO-) generation with great cytotoxicity. At the same time, the nanostructure also degrades gradually, leading to high elimination (94.6%) via feces and urine within 14-day. The synergistic NO and chemo-/sono-dynamic therapy brings prominent antitumor efficiency and further activates the immune response to inhibit metastasis and recurrence. This work develops a family of NO donors that would further widen the application of NO therapy in other fields.

Pathways of lymph node metastasis and prognosis after right hemicolectomy for cecal cancer: results from a retrospective single center.

BACKGROUND: The recommended operation for cecum cancer (CC) is right hemicolectomy (RH) in some Western countries while the principle of D3 lymphadenectomy in Japan recommends resecting approximately 10 cm from the tumor edge. Therefore, the optimal surgical approach for cecum cancer (CC) remains controversial. We conducted this retrospective study to explore the pattern of lymph node metastasis and better surgical procedures for CC. METHODS: A total of 224 cecum cancer patients from January 1, 2014, to December 31, 2021, were retrospectively included in the final study. The pattern of lymph node metastasis (LNM) was investigated. RESULTS: A total of 113 (50.4%, 113/224) patients had pathologically confirmed LNM. The most frequent metastatic site was no. 201 lymph node (46%, 103/224), while 20 (8.9%, 20/224) patients had LNM in no. 202 lymph node, and 8 (3.6%, 8/224) patients had LNM in no. 203 lymph node. Only 1 (0.4%, 1/224) patient had LNM in no. 221 lymph node, four (1.8, 4/224%) patients had LNM in no. 223 lymph node, and no patients had LNM in no. 222 lymph node. LNM in no. 223 lymph node was significantly associated with a poor prognosis. Multivariate analysis indicated that LNM in no. 223 lymph node (HR = 4.59, 95% CI 1.18-17.86, P = 0.028) was the only independent risk factor associated with worse disease-free survival (DFS). CONCLUSIONS: The LNM in no. 223 lymph node for cecum cancer was rare. Therefore, standard right hemicolectomy excision is too extensive for most CC cases.

Multi-Omic Integration of Blood-Based Tumor-Associated Genomic and Lipidomic Profiles Using Machine Learning Models in Metastatic Prostate Cancer.

PURPOSE: To determine prognostic and predictive clinical outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castrate-resistant prostate cancer (mCRPC) on the basis of a combination of plasma-derived genomic alterations and lipid features in a longitudinal cohort of patients with advanced prostate cancer. METHODS: A multifeature classifier was constructed to predict clinical outcomes using plasma-based genomic alterations detected in 120 genes and 772 lipidomic species as informative features in a cohort of 71 patients with mHSPC and 144 patients with mCRPC. Outcomes of interest were collected over 11 years of follow-up. These included in mHSPC state early failure of androgen-deprivation therapy (ADT) and exceptional responders to ADT; early death (poor prognosis) and long-term survivors in mCRPC state. The approach was to build binary classification models that identified discriminative candidates with optimal weights to predict outcomes. To achieve this, we built multi-omic feature-based classifiers using traditional machine learning (ML) methods, including logistic regression with sparse regularization, multi-kernel Gaussian process regression, and support vector machines. RESULTS: The levels of specific ceramides (d18:1/14:0 and d18:1/17:0), and the presence of CHEK2 mutations, AR amplification, and RB1 deletion were identified as the most crucial factors associated with clinical outcomes. Using ML models, the optimal multi-omics feature combination determined resulted in AUC scores of 0.751 for predicting mHSPC survival and 0.638 for predicting ADT failure; and in mCRPC state, 0.687 for prognostication and 0.727 for exceptional survival. The models were observed to be superior than using a limited candidate number of features for developing multi-omic prognostic and predictive signatures. CONCLUSION: Using a ML approach that incorporates multiple omic features improves the prediction accuracy for metastatic prostate cancer outcomes significantly. Validation of these models will be needed in independent data sets in future.

Defect-Rich Ni-CoO@PEG Porous Hexagonal Nanosheets: Multi-enzyme and Ultrasound Catalysis for Synergistic Anticancer Treatment.

Given the similarity with photocatalysis, sonodynamic therapy (SDT) can be defined as ultrasonic (US) catalysis. Encouraged by the principles of photocatalysis and defect chemistry, defect-rich nickel (Ni)-doped cobaltous oxide (Ni-CoO@PEG) porous hexagonal nanosheets have been synthesized as a sonosensitizer. The doping of Ni decreases the band gap that is testified by density functional theory to increase the US-generated charges. Under US irradiation, Ni-CoO@PEG nanosheets produce 1O2 as an active species that is determined by dissolved O2 and electrons. Moreover, the doping also brings abundant oxygen vacancies (OV) that not only are in favor of efficient separation of electron-hole but also enhance the interaction toward O2, boosting 1O2 generation. In addition, Ni-CoO@PEG shows robust mimic catalase (CAT) and peroxidase characterization to effectively improve the intratumor O2 content and oxidation stress. What is more, the nanosheets also possess glucose oxidase activity that can consume glucose to elevate the H2O2/acid level and to block the intracellular energy supply. The tandem nanozyme behaviors would further regulate the tumor microenvironment for assisting anticancer treatment. It is noted that Ni-CoO@PEG reveals a novel half-metallic feature endowing great magnetism and magnetic resonance imaging capacity. The above synergistic treatments exhibit outstanding anticancer performance that also evokes antitumor immunity to suppress metastasis and recurrence, efficiently.

NIR-II driven photocatalytic hydrogen peroxide-supply on metallic copper-nickel selenide (Cu-Ni0.85Se) nanoparticle for synergistic therapy.

Currently, finite intratumoral H2O2 content has restricted the efficacy of chemodynamic therapy (CDT). Here, Cu-Ni0.85Se@PEG nanoparticles are constructed to display intracellular NIR-II photocatalytic H2O2 supplement. The formation mechanism is explored to discover that H2O2 generation is dominated by photo-excited electrons and dissolved O2 via a typical sequential single-electron transfer process. Both density functional theory calculation and experimental data confirm its metallic feature that endows the great NIR-II absorption and photothermal conversion efficiency (59.6 %, 1064 nm). Furthermore, the photothermal-assisting consecutive interband and intraband transition in metallic catalyst contributes to the high redox capacity and efficient separation/transfer ability of photo-generated charges, boosting H2O2 production under 1064 nm laser irradiation. In addition, Cu-Ni0.85Se@PEG possess mimic peroxidase and catalase activity, leading to in-situ H2O2 activation to produce ∙OH and O2 for the enhanced CDT and hypoxia relief. What's more, the nanomaterials reveal novel biodegradation that is derived from oxidation from insolvable selenide into soluble selenate, resulting in elimination via feces and urine within 2 weeks. Synergistic CDT and photothermal therapy (PTT) further lead to great tumor inhibition and immune response for anti-tumor. The antitumor mechanism and the potential biological process also are investigated by high-throughput sequencing of expressed transcripts (RNAseq). The great treatment performance is responsible for the regulation of related oxidative stress and stimulus genes to induce organelle (mitochondrial) and membrane dysfunction. Besides, the synergistic therapy also can efficiently evoke immune response to further fight against tumor.

Hollow CoP@N-Carbon Nanospheres: Heterostructure and Glucose-Enhanced Charge Separation for Sonodynamic/Starvation Therapy.

Sonodynamic therapy (SDT) can be described as ultrasonic (US) catalysis. Adequate charge separation is considered as effective means to promote reactive oxygen species (ROS). Here, hollow CoP@N-carbon@PEG (CPCs@PEG) nanospheres (∼60 nm) are prepared as sonosensitizers, showing greater ROS generation than pure CoP@PEG under US irradiation. Both 1O2 and ·O2- are activation species that are determined by O2 and electrons. The great SDT performance of CPCs@PEG is ascribed to the heterostructure which promotes the separation and transfer for US-generated electrons and holes. In addition, holes can be further captured by endogenous glucose that is in favor of electron aggregation and ROS generation. Moreover, the consumption of glucose would decrease intracellular ATP for starvation therapy. Given the higher oxidation ability of Co3+, CPCs@PEG nanospheres possess catalase (CAT) activity to convert H2O2 into O2 for assisting ROS generation. Moreover, they also can oxidize glutathione (GSH) as a mimic GSH oxidase to break intratumor redox balance, facilitating oxidative stress. More importantly, the nanocomposites reveal good degradation ability dominated by the oxidation from insoluble phosphide into soluble phosphate, accelerating elimination via urine and feces within 14 days. CPCs@PEG nanospheres integrate the above effects not only to reveal great tumor inhibition ability but also to excite immune activation for anticancer.

Minimally invasive para-aortic lymph node dissection in left-sided colonic and rectal cancer: experience based on a high-volume centre.

AIM: There is no established consensus on the optimal surgical approach to para-aortic lymph node (PALN) dissection in patients with colorectal cancer. This study aimed to demonstrate the technical and oncological safety of minimally invasive PALN dissection for left-sided colonic and rectal cancer patients with clinically suspected infrarenal PALN metastasis. METHOD: One hundered and one patients who underwent primary tumour resection and minimally invasive (laparoscopic n = 92, robotic n = 9) PALN dissection for left-sided colonic and rectal cancer were included. Logistic regression analysis was used to identify risk factors for PALN metastasis. Survival outcomes were evaluated using the Kaplan-Meier (log-rank) method. RESULTS: Para-aortic lymph node metastasis was pathologically confirmed in 23 patients (22.8%). Postoperative complications occurred in 22 patients (21.8%). Pathological N2 stage (OR = 9.337, p = 0.003) and inferior mesenteric artery LN metastasis (OR = 7.499, p = 0.009) were independently associated with PALN metastasis. The median follow-up time was 32 months (range 3-92 months). In all patients, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 76.1% and 69.5%, respectively. The 5-year OS and PFS rates in patients with PALN metastasis were 49.8% and 47.5%, respectively. Patients with PALN metastasis had lower 5-year OS (p = 0.023) and PFS rates (p = 0.035) than those without PALN metastasis. CONCLUSION: Minimally invasive PALN dissection had acceptable postoperative complications and may be oncologically beneficial in selected patients with clinically suspicious PALN metastasis.

Z-scheme MoS2/Co3S4@PEG nanoflowers: Intracellular NIR-II photocatalytic O2 production facilitating hypoxic tumor therapy.

Intratumoral hypoxia, which is in favour of cancer cell proliferation, invasion and metastasis, also inhibits photodynamic therapy (PDT) badly. Herein, second near-infrared (NIR-II) photocatalytic O2 production is established to realize hypoxia relief. MoS2/Co3S4@PEG (MSCs@PEG) nanoflowers (100-150 nm) are prepared via a two-step hydrothermal method. These samples possess high NIR-II harvest and photothermal conversion (39.8 %, 1064 nm) ability. That not only reveals photothermal therapy (PTT) but also lifts the thermal energy of nanomaterials to replenish extra energy, making sure the co-excitation of MoS2 (1.14 eV) and Co3S4 (1.40 eV) by low-energy NIR-II (1064 nm, 1.16 eV) laser. The investigation of band structure further displays the Z-Scheme characterization of MSCs heterostructure. These photo-excited holes/electrons hold great redox ability to form O2 (water splitting) and reactive oxygen species (ROS), simultaneously. In addition, MSC-2@PEG can be served to mimic catalase, peroxidase, and glutathione (GSH) oxidase to further boost oxidative stress. It is noted that heterostructure discovers the greater nanozyme activity, attributing to the lower resistance for charge transfer. Moreover, MSC-2@PEG displays a novel biodegradation ability to induce the elimination via urine and faeces within 14 days. Given the superparamagnetic and photothermal effect, the nanocomposite can be used as magnetic resonance and photothermal imaging (MRI and PTI) contrast. Associated with dual-imaging, intracellular O2 supplementation, and synergistic chemotherapy (CDT)/PTT/PDT, MSC-2@PEG possess great tumor inhibition that also efficiently motivates immune response for anticancer.

A refined prediction of early recurrence combining tumor deposits in patients with resected rectal mucinous adenocarcinoma.

PURPOSE: Early recurrence (ER) of rectal mucinous adenocarcinoma (MAC) has yet to be defined. We therefore explored risk factors for ER and constructed a predictive nomogram. METHOD: A total of 145 rectal MAC patients undergoing radical surgery were included. The minimum P value method was used to determine the optimal cut-off point to discriminate between ER and late recurrence (LR). Risk factors for ER were determined by a logistic regression analysis, and a predictive nomogram was constructed. RESULTS: A total of 62 (42.8%) patients developed tumor recurrence. The optimal time to define ER was 12 months. A pre-treatment tumor distance from the anal verge ≤ 7 cm, pathological N stage, lymphovascular invasion, tumor deposits, and time to recurrence ≤ 12 months were significantly associated with a poor post-recurrence survival in patients with recurrence. A pre-treatment serum carcinoembryonic antigen (CEA) level > 10 ng/ml, pre-treatment tumor distance from the anal verge ≤ 7 cm, pathological N + stage, perineural invasion, and tumor deposits were identified as independent risk factors associated with ER. A nomogram predicting ER was constructed (C-index 0.870). CONCLUSION: The pre-treatment serum CEA level, pre-treatment tumor distance from the anal verge, pathological N + stage, perineural invasion, and tumor deposits were significantly predictive of ER for rectal MAC patients.

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors.

Although phototherapy has attracted extensive attention in antitumor field in recent years, its therapeutic effect is usually unsatisfactory because of the complexity and variability of the tumor microenvironment (TME). Herein, we report novel CoSn(OH)6@CoOOH hollow carriers with oxidase properties that can enhance phototherapy. Hollow CoSn(OH)6@CoOOH nanocubes (NCs) with a particle size of ∼160 nm were synthesized via a two-step process of coprecipitation and etching. These NCs can react with O2 to generate singlet oxygen without hydrogen peroxide and consume glutathione, and their hollow structure can be utilized to carry drug molecules. After loading indocyanine green (ICG) and 1,2-bis(2-(4,5-dihydro-1H-imidazol-2-yl)propan-2-yl) diazene dihydrochloride (AIPH), the resulting nanosystem (HCIA) exhibited enhanced phototherapy effects through the catalytic activity of oxidase, production of alkyl radicals, and consumption of glutathione. Cell and mouse experiments showed that HCIA combined with near-infrared laser irradiation significantly inhibited the growth of 4T1 tumors. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that PI3K-Akt and MAPK signaling pathways were highly relevant to this therapeutic system. Such hollow NCs with oxidase activity have considerable potential for the design of multifunctional drug delivery vehicles for tumor therapy.

Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin.

Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23−52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate.

Biodegradation Mn-CoS@carbon di-shell nanoheterostructure with enhanced nanozyme-mediated phototherapy.

The efficacy of phototherapy is dependent on intracellular O2 concentration and NIR harvest. Here, a simple nanoplatform with nanoenzyme mediated phototherapy enhances anticancer capacity. Mn-CoS@carbon (CMS/C) di-shell hollow nanospheres (50 nm) are synthesized successfully through two-step consecutive Kirkendall process. The nanoheterostructure reveals the higher near-infrared (NIR) light absorption and photothermal conversion rate of 66.3% than pure CoS (45.5%), owing to the decreased band gap and multi-reflection of incident light in the hollow structure. And CMS/C reveals the reactive oxygen species (ROS) production and nanoenzyme activities (mimic peroxidase and catalase) that are 6 and 2 times than those of pure CoS. Furthermore, the nanoenzyme exhibits NIR-enhanced abilities to produce more OH and O2 facilitating anticancer. In addition, it also depletes glutathione (mimicking glutathione oxidase), to disturb intracellular redox-homeostasis, boosting the increase of oxidative stress. With grafting bovine serum albumin (BSA) and drug loading, CMS/C@BSA-Dox integrated multi-therapy make the great anticancer effect in vitro and vivo. After that, the nanocomposite could be biodegraded and eliminated via urinary and feces within 14 days. Based on this work, the efficient charge-separation can be designed to reveal high performance nanoenzymes as well as photosensitizers for anticancer.

NIR-II-driven intracellular photocatalytic oxygen-generation on Z-Scheme iron sulfide/cobalt sulfide nanosheets for hypoxic tumor therapy.

Tumor hypoxia not only promotes the proliferation, invasion and metastasis of cancer cells but also seriously hinders photodynamic therapy (PDT). Here, second near-infrared (NIR-II) photocatalytic O2 generation is introduced to relieve hypoxia. FeS2/CoS2@PEG (FCs@PEG) nanosheets (∼80 nm) are prepared with Fe-Co layered double hydroxides (LDHs) as precursor. As-synthesized samples have great NIR-II harvest and photothermal conversion efficiency (50.5 %, 1064 nm). In addition, photothermal effect can elevate the thermal energy of nanocomposite to supply extra energy and to excite FeS2 (1.16 eV) and CoS2 (1.37 eV) simultaneously by low-energy NIR-II (1064 nm, 1.16 eV) irradiation. Band structure is further investigated to discover the Z-Scheme mechanism of FCs@PEG, whose photogenerated charges remains high redox potential to oxidize water forming O2 and to capture O2 producing reactive oxygen species (ROS), respectively. In addition, FC2@PEG enhances peroxidase and catalase activities attributing to the lower resistance for charge transfer in heterostructure. Besides, the nanocomposite also can be used as glutathione oxidase (GSHOD) to deplete GSH and break intracellular redox balance, facilitating oxidative stress. Most importantly, FC2@PEG reveals excellent biodegradation and elimination via feces and urine within 14 D. FCs@PEG integrate magnetic resonance and photothermal imaging (MRI and PTI), O2 in situ supply, and synergistic photothermal therapy (PTT)/PDT/chemotherapy (CDT) to arouse immune response for anticancer.