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Simple Summary: Leiomyosarcoma (LMS) is thought to be an immune cold tumor that generally does not respond to immune checkpoint inhibitors (ICIs). To date, there is no validated immune biomarker used in LMS patients. The tertiary lymphoid structure (TLS) is the only potential predictive biomarker, but rarely present in LMS. Our study is the first study to investigate the immune biomarker using comprehensive transcriptomic profiling solely focused on tumor immune microenvironment (TIME) in LMS. Our study identified a subset of LMS with an active ("hot") tumor immune microenvironment (TIME) that is consistently associated with several immune signatures validated in other cancers in the clinical setting. Our study supports the further development of TIME multi-gene immune signature predictive biomarker that can be embedded in the future prospective clinical trials to evaluate its clinical utility to select LMS patients for ICIs. Purpose: To investigate the immune biomarker in Leiomyosarcoma (LMS), which is rare and recognized as an immune cold cancer showing a poor response rate (<10%) to immune checkpoint inhibitors (ICIs). However, durable response and clinical benefit to ICIs has been observed in a few cases of LMS, including, but not only, LMS with tertiary lymphoid structure (TLS) structures. Patients and methods: We used comprehensive transcriptomic profiling and a deconvolution method extracted from RNA-sequencing gene expression data in two independent LMS cohorts, the International Cancer Genome Consortium (ICGC, N = 146) and The Cancer Genome Atlas (TCGA, N = 75), to explore tumor immune microenvironment (TIME) in LMS. Results: Unsupervised clustering analysis using the previously validated two methods, 90-gene signature and Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), identified immune hot (I-H) and immune high (I-Hi) LMS, respectively, in the ICGC cohort. Similarly, immune active groups (T-H, T-Hi) were identified in the TCGA cohort using these two methods. These immune active ("hot") clusters were significantly associated, but not completely overlapping, with several validated immune signatures such as sarcoma immune class (SIC) classification and TLS score, T cell inflamed signature (TIS) score, immune infiltration score (IIS), and macrophage score (M1/M2), with more patients identified by our clustering as potentially immune hot. Conclusions: Comprehensive immune profiling revealed a subset of LMS with a distinct active ("hot") TIME, consistently associated with several validated immune signatures in other cancers. This suggests that the methodologies that we used in this study warrant further validation and development, which can potentially help refine our current immune biomarkers to select the right LMS patients for ICIs in clinical trials. [ABSTRACT FROM AUTHOR]

PURPOSE: To investigate the use of PTEN biomarker to improve prognostic stratification in patients with localized gastrointestinal stromal tumor (GIST). METHODS: PTEN expression and genomic analysis were performed on two independent GIST-60 (n = 60) and GIST-100 (n = 100) cohorts, respectively. RESULTS: PTEN expression was significantly lower in patients with local and metastatic recurrent tumor compared with those with no recurrence (P =.004). PTEN low expression was significantly associated with poor disease-free survival (DFS) compared with PTEN high expression (43.73 v 117.95 months; P =.0084) and distant metastatic-free survival (DMFS; 57.95 v 117.95 months; P =.0032). PTEN heterozygous loss was observed in approximately 10% of the patients in each cohort and was associated with poor DFS compared with patients with PTEN normal status (27.56 months v not reached [NR]; P <.001) and DMFS (27.56 months v NR; P <.001). Multivariate analysis revealed that PTEN expression was an independent clinical prognosis factor besides tumor size, mitosis index, and location (hazard ratio for DFS: 3.8; P =.033; hazard ratio for DMFS 5.7, P =.01). Furthermore, PTEN low expression was independently associated with poor DMFS in clinically high-risk patients (mDMFS: 42.28 v 65.61 months; P =.0166). In addition, PTEN heterozygous loss was independently associated with poor DMFS in patients at either low/intermediate risk (mDMFS: 18.05 months for PTEN loss v NR for PTEN normal status; P <.001) or at high risk (mDMFS: 27.19 months for PTEN loss v 105.36 months for PTEN normal status; P =.044). CONCLUSION: PTEN low expression/gene loss is an independent significant prognostic factor and a promising component to strengthen the clinical prognostic tools in patients with localized GIST. PTEN biomarker refines the standard clinical prognostic tools and may help guide clinical management for resected GISTs. [ABSTRACT FROM AUTHOR]

Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely. [ABSTRACT FROM AUTHOR]

Metastasis is a major dilemma of cancer therapy. It frequently occurs in breast cancer, which is the leading form of malignant tumor among females worldwide. Although there are therapies that provide a possible method for this challenge, such as chemotherapy, the tumoral metabolic pathway is unconventional and favors metastasis and proliferation. This magnifies the difficulty of treating breast cancer. In this study, we identified 2-deoxyglucose (2 DG) as an important glycolysis suppressor that can potentiate sonodynamic therapy (SDT) to inhibit migration and invasion. In addition, disruptions of the cell membrane microstructure were captured by a scanning electron microscope in cells treated with the co-therapy. Similarly, we detected blockages of the cell cycle process, using flow cytometry. Of note, we observed that hexokinase II (HK2), the rate-limiting enzyme of glycolysis, was notably uncoupled from the mitochondria in SDT + 2 DG co-therapy group. Furthermore, there was altered expression of HK2 and Glut1, which control glycolysis. Simultaneously, the in vivo results revealed that pulmonary metastasis was also seriously suppressed by SDT + 2 DG co-therapy. These results demonstrate this co-therapy is a promising strategy for breast cancer inhibition through metastasis and proliferation. [ABSTRACT FROM AUTHOR]

PURPOSE: This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options. METHODS: Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing. RESULTS: The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA–damaging agents. CONCLUSION: Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Chronic primary insomnia (CPI) is a commonly encountered clinical disease, the incidence of which has been rising in recent years. In theoretical contexts, the temperature of acupoints in CPI patients is higher than that in unaffected individuals together with concomitant increases in fatigue index and intracranial arterial velocity. Acupuncture has long been used to treat insomnia, and the sleep three-needle acupuncture (STA) approach represents one promising such treatment for this condition. However, no studies to date have assessed the ability of this technique to lower acupoint temperature values or to improve the Insomnia Severity Index (ISI) in treated individuals. Methods: The present exploration is a prospective, randomized, assessor-blind, controlled trial. Totally, 102 adult patients with CPI will be recruited with varying levels of insomnia severity (mild, moderate, severe) and randomized into six equally sized groups. Patients in these groups will then undergo STA together with cognitive-behavioral therapy (CBT) or CBT alone. Acupuncture will be administered for 30 min per treatment 2–3 times per week (7 days per cycle) for a maximum of 10 sessions in 4 cycles. All patients underwent CBT for 4 weeks. In addition, 17 patients will be recruited for a healthy control group. Primary outcomes will include acupoint temperature variations and ISI values, while secondary outcomes will include fatigue index values, intracranial arterial velocity, and Pittsburgh Sleep Quality Index (PSQI) values. Discussion: This study aims to test the theory that STA can lower acupoint temperatures and improve ISI values in CPI patients. Trial registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn), ID: ChiCTR2100048704. Registered on 13/07/2021. [ABSTRACT FROM AUTHOR]

Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at least in part. Recent studies suggest that dual restriction of glycolysis and mitochondrial function may overcome this issue. Sonodynamic therapy (SDT), a prospective therapeutic modality for cancers, has been reported to induce mitochondria-dependent cell damage. Here, we investigated the combined effect of SDT and 2-deoxyglucose (2DG), an anti-glycolytic agent, on breast cancer both in vitro and in vivo. In vitro, we found that, compared with a single treatment, SDT + 2DG co-treatment significantly decreased cell viability and increased cell apoptosis. Moreover, the generation of reactive oxygen species was enhanced and mitochondrial membrane potential (MMP) was reduced after SDT + 2DG co-treatment. Furthermore, the oxidative phosphorylation was also restrained after SDT + 2DG co-treatment, further to cause the blockage of ATP provision. In vivo, SDT + 2DG markedly reduced tumor volume and weight, consistent with the in vitro findings. Furthermore, toxicology tests concurrently indicated that the dosages of sinoporphyrin sodium and 2DG were comparatively tolerable. Generally, these results indicated that SDT + 2DG combination therapy may be an available, promising therapy for highly metastatic breast cancer. [ABSTRACT FROM AUTHOR]

In this work, we demonstrate that solid-base such as amino-modified silica aerogel (SA-NH 2 ) together with trace water showed excellent catalytic performance in one-pot sequential reaction of acid-catalyzed benzaldehyde dimethyl acetal hydrolysis and base-catalyzed Henry reaction which was usually catalyzed by acid-base bifunctional heterogeneous catalyst. The role of trace water in the reaction was discussed by batch control experiment. This SA-NH 2 /water catalytic system showed high reactant conversions (> 99%) and main product selectivities (up to 99.4%). The trace water induced acid catalysis mechanism and a possible H + /-NH 2 coexistence mechanism were given to explain the synergistic catalytic effect of solid-base and trace water. [ABSTRACT FROM AUTHOR]

Most cancer cells have the specially increased glycolytic phenotype, which makes this pathway become an attractive therapeutic target. Although glycolytic inhibitor 2-deoxyglucose (2-DG) has been demonstrated to potentiate the cytotoxicity of photodynamic therapy (PDT), the impacts on cell migration after the combined treatment has never been reported yet. The present study aimed to analyze the influence of glycolytic inhibitors 2-DG and 3-bromopyruvate (3-BP) combined with Ce6-PDT on cell motility of Triple Negative Breast Cancer MDA-MB-231 cells. As determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium-bromide-Tetraz-olium (MTT) assay, more decreased cell viability was observed in 2-DG + PDT and 3-BP + PDT groups when compared with either monotherapy. Under optimal conditions, synergistic potentiation on cell membrane destruction and the decline of cell adhesion and cells migratory ability were observed in both 2-DG + PDT and 3-BP + PDT by electron microscope observation (SEM), wound healing and trans-well assays. Besides, serious microfilament network collapses as well as impairment of matrix metalloproteinases-9 (MMP-9) were notably improved after the combined treatments by immunofluorescent staining. These results suggest that 2-DG and 3-BP can both significantly potentiated Ce6-PDT efficacy of cell migration inhibition. [ABSTRACT FROM AUTHOR]

Malignant cells are highly dependent on aerobic glycolysis, which differs significantly from normal cells (the Warburg effect). Interference of this metabolic process has been considered as an innovative method for developing selective cancer therapy. A recent study demonstrated that the glycolysis inhibitor 2-deoxyglucose (2-DG) can potentiate PDT efficacy, whereas the possible mechanisms have not been carefully investigated. This study firstly proved the general potentiation of PDT efficacy by 2-DG and 3-bromopyruvate (3-BP) in human breast cancer MDA-MB-231 cells, and carefully elucidated the underlying mechanism in the process. Our results showed that both 2-DG and 3-BP could significantly promote a PDT-induced cell cytotoxic effect when compared with either monotherapy. Synergistic potentiation of mitochondria- and caspase-dependent cell apoptosis was observed, including a mitochondrial membrane potential (MMP) drop, Bax translocation, and caspase-3 activation. Besides, ROS generation and the expression of oxidative stress related proteins such as P38 MAPK phosphorylation and JNK phosphorylation were notably increased after the combined treatments. Moreover, when pretreated with the ROS scavenger N-acetylcysteine (NAC), the ROS generation, the MMP drop, cell apoptosis and cytotoxicity were differently inhibited, suggesting that ROS was vertical in the pro-apoptotic process induced by 2-DG/3-BP combined with PDT treatment. These results indicate that the combination of glycolytic antagonists and PDT may be a promising therapeutic strategy to effectively kill cancer cells. [ABSTRACT FROM AUTHOR]

Primary pericardial malignant mesothelioma (PMPM) is extremely rare with an incidence less than 0.0022%. It comprises 0.7% of all mesothelioma cases. To date, approximately 350 cases of pericardial mesothelioma have been reported in the literature. Its typical presentation is insidious, with nonspecific signs and symptoms, and usually results in constrictive pericarditis, cardiac tamponade and congestive heart failure either by a serous effusion or by direct tumorous constriction of the heart. With the exception of several case reports, the outcome is uniformly fatal, and patients typically die within six months of diagnosis. Here we report a 72-year-old Cauca - sian male with persistent pericardial and pleural effusion. He was diagnosed with PMPM after pericardectomy. He had only one cycle of chemotherapy with cisplatin and pemetrexed. He developed acute kidney injury as result of chemotherapy. He died 1 month after diagnosis and 6 months after the first symptoms. [ABSTRACT FROM AUTHOR]

The INhibitor of Growth tumor suppressors (ING1-ING5) affect aging, apoptosis, DNA repair and tumorigenesis. Plant homeodomains (PHD) of ING proteins bind histones in a methylation-sensitive manner to regulate chromatin structure. ING1 and ING2 contain a polybasic region (PBR) adjacent to their PHDs that binds stress-inducible phosphatidylinositol monophosphate (PtIn-MP) signaling lipids to activate these INGs. ING1 induces apoptosis independently of p53 but other studies suggest proapoptotic interdependence of ING1 and p53 leaving their functional relationship unclear. Here we identify a novel ubiquitin-binding domain (UBD) that overlaps with the PBR of ING1 and shows similarity to previously described UBDs involved in DNA damage responses. The ING1 UBD binds ubiquitin with high affinity (Kd,100 nM) and ubiquitin competes with PtIn-MPs for ING1 binding. ING1 expression stabilized wild-type, but not mutant p53 in an MDM2- independent manner and knockdown of endogenous ING1 depressed p53 levels in a transcription-independent manner. ING1 stabilized unmodified and six multimonoubiquitinated forms of wild-type p53 that were also seen upon DNA damage, but not p53 mutants lacking the six known sites of ubiquitination. We also find that ING1 physically interacts with herpesvirus-associated ubiquitin-specific protease (HAUSP), a p53 and MDM2 deubiquitinase (DUB), and knockdown of HAUSP blocks the ability of ING1 to stabilize p53. These data link lipid stress signaling to ubiquitin-mediated proteasomal degradation through the PBR/UBD of ING1 and further indicate that ING1 stabilizes p53 by inhibiting polyubiquitination of multimonoubiquitinated forms via interaction with and colocalization of the HAUSP-deubiquitinase with p53. [ABSTRACT FROM AUTHOR]

Precise targeting and high therapeutic efficiency are the major requisites of personalized cancer treatment. However, some unique features of the tumor microenvironment (TME) such as hypoxia, low pH and elevated interstitial fluid pressure cause cancer cells resistant to most therapies. Bacteria are increasingly being considered for targeted tumor therapy owing to their intrinsic tumor tropism, high motility as well as the ability to rapidly colonize in the favorable TME. Compared to other nano-strategies using peptides, aptamers, and other biomolecules, tumor-targeting bacteria are largely unaffected by the tumor cells and microenvironment. On the contrary, the hypoxic TME is highly conducive to the growth of facultative anaerobes and obligate anaerobes. Live bacteria can be further integrated with anti-cancer drugs and nanomaterials to increase the latter's targeted delivery and accumulation in the tumors. Furthermore, anaerobic and facultatively anaerobic bacteria have also been combined with other anti-cancer therapies to enhance therapeutic effects. In this review, we have summarized the applications and advantages of using bacteria for targeted tumor therapy (Scheme 1) in order to aid in the design of novel intelligent drug delivery systems. The current challenges and future prospects of tumor-targeting bacterial nanocarriers have also been discussed. [ABSTRACT FROM AUTHOR]

The ING family of proteins are involved in chromatin remodelling, and bind to and affect the activity of histone acetyltransferase, histone deacetylase, and factor acetyltransferase protein complexes. Some family members affect transcription, including the expression of p53-inducible genes such as p21 and Bax, and ING2 induces p53 acetylation on a site implicated in the regulation of p53 activity. ING1 promotes DNA repair and interacts with proliferating cell nuclear antigen, thus linking DNA repair, apoptosis and chromatin remodelling. Here, we summarize what is known about the molecular interactions of ING1 family proteins and, based on these interactions, develop a model to better understand the impact of ING proteins on multiple biological processes. [Copyright &y& Elsevier]

Spinal cord injury (SCI) is one of the most devastating diseases that challenges neurology and medicine, leading to paraplegia or quadriplegia worldwide. Neuroprotection conferred by histone deacetylase (HDAC) inhibitors against various insults and deficits in the central nervous system has been reported previously. Herein, we set out to ascertain whether HDAC3 inhibition exerts neuroprotective effects against SCI. A modified Allen's weight-drop method was performed to induce experimental SCI in rats. Basso-Beattie-Bresnahan (BBB) scores were used to assess locomotor function. Flow cytometric analysis of AnnexinV-FITC/PI double staining, TUNEL staining, and immunoblotting analysis of apoptosis-related proteins were performed to determine apoptosis in H 2 O 2 -induced cell injury of primary rat neurons. Upregulated HDAC3 and downregulated miR-27a were observed in spinal cord tissues of SCI rats and H 2 O 2 -injured neurons. HDAC3 knockdown by its specific shRNA restored the locomotor function of SCI rats and prevented rat neurons from H 2 O 2 -induced apoptosis through promotion of miR-27a. miR-27a targeted PAK6 (encoding P21-activated kinase 6) and inhibited its expression. The effects of HDAC3 knockdown on the locomotor function of SCI rats and H 2 O 2 -induced apoptosis of rat neurons were lost upon further PAK6 overexpression. The present study uncovers that silencing HDAC3 inhibited PAK6 expression by upregulating miR-27a, eventually inhibiting neuron apoptosis and promoting the recovery of SCI, which might provide a novel therapeutic target for SCI. [ABSTRACT FROM AUTHOR]

Objectives: We conducted a retrospective multi‐centre study to assess the real‐world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra‐skeletal mesenchymal CS (ESMC). Methods: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12–76); median starting dose was 60 mg for CABO (n = 37, range 40–60) and 120 mg for REGO (n = 29, range 40–160). Twenty‐eight (42.4%) patients required dose reduction: hand‐foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7–13.1); 13.4 months (n = 18, 95% CI 3.4–27.2), 8.1 (n = 4, 95% CI 4.1–9.3) and 18.2 (n = 5, 95% CI (10.4–na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8–5), 3.9 (n = 18, 95% CI 2.1–5.9), 5.53 (n = 4. 95% CI 2.13–NA) and 11.4 (n = 5, 95% CI 1.83–14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. Conclusion: Our real‐world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research. Real‐world national CanSaRCC data support the use of regorafenib and cabozantinib in children and adults with relapsed bone sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Traditional musk is a scarce resource of traditional Chinese medicine in China, which is difficult to obtain. Few studies have been reported on the search for alternatives to musk. To this end, we collected muskrat musk, which is widely regarded as a substitute for musk, and performed Gas Chromatography Time-of-Flight Mass Spectrometry (GC–TOF–MS) metabolomics analysis together with musk. The results showed that muskrat musk and musk had certain similarities in terms of their composition, but the important active components of muscone were missing. Analysis of muskrat musk at different ages showed that amino acids, fatty acids, and steroids were significantly enriched, which may affect the function of muskrat scent glands through local enrichment for a short time. Muskrat musk is considered to be a potential substitute for traditional musk. However, little is known about the similarity between muskrat musk and musk, and whether it is related to muskrat age. In this study, muskrat musk (MR1, MR2, and MR3) were from 1, 2, and 3-year-old muskrats, respectively, and white musk (WM) and brown musk (BM) were picked from male forest musk deer. The results indicated that muskrat musk had higher similarity to WM than BM. Further research showed that RM3 had the highest matched degree with WM. By significantly different metabolite analysis, we found that 52 metabolites continue to increase from 1- to 3-year-old muskrats. In total, 7 and 15 metabolites were significantly decreased in RM1 vs. RM2 and RM2 vs. RM3, respectively. Meanwhile, 30 and 17 signaling pathways were observed from increased and decreased metabolites, respectively. The increased metabolites mainly entailed enrichment in amino acid biosynthesis and metabolism, steroid hormone biosynthesis, and fatty acid biosynthesis. In conclusion, muskrat musk from three-year-old muskrat is a relatively good substitute for white musk, and the result also implies that these biological processes of amino acid biosynthesis and metabolism, steroid hormone biosynthesis, and fatty acid biosynthesis are beneficial to the secretion of muskrat musk. [ABSTRACT FROM AUTHOR]

Mirroring the rapid clinical performance, immune checkpoint blockade (ICB) leads a remarkable clinical advance in combating cancer, but suffers poor response in most cancers. The low presence of tumor-infiltration lymphocytes and the poor immunogenicity in tumor microenvironment (TME) are the main factors hindering the effectiveness of ICB in the treatment of immunological "cold" tumors. Aiming at boosting immune response via TME modulation, we report a near-infrared laser-guided photoimmuno-strategy in which synergistic phototherapy, immune adjuvant, and ICB are integrated into one versatile nanoporphyrin platform. The prepared nanoporphyrins are self-assembled from purpurin18-lipids and have photodynamic/photothermal and immunomodulatory effects that can be tuned under a single laser irradiation, concomitant with fluorescence or MSOT imaging. In this work, the contributions of each component in the nanoporphyrin platform were specified. In particular, phototherapy-driven in situ tumor cell death provided abundant tumor-associated antigens to initiate immune responses. With the assist of spatiotemporally delivered immune adjuvant, phototherapy potentiated tumor immunogenicity, reprogrammed "cold" tumors into "hot" ones, and sensitized tumors to ICB therapy. Further combined with PD-L1 blockade, the photoimmune-strategy substantially stimulated tumor-specific immune-responses and long-term immunological memory against primary tumor, abscopal tumor as well as metastatic foci. Such single light-primed photoimmunotherapy offers a promising solution to overcome common hurdles in ICB treatment and can potentially be integrated into existing clinical practice. [Display omitted] • Nanoporphyrins were developed for dual-mode imaging, PDT & mild PTT, and controlled delivery of immunomodulators. • A beam of light on the nanoporphyrin platform stimulated intense tumor cell death and immune activation. • The laser-driven immune response and reshaped tumor environment facilitated ICB therapy of cold tumors. • The photoimmunotherapy elicited cooperative and long-lasting antitumor effects in primary, abscopal and metastatic tumors. [ABSTRACT FROM AUTHOR]

Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was − 8.5 % (range −100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined. • Sorafenib and pazopanib are effective treatments for desmoid tumor patients. • Treatment discontinuation should be discussed in radiologically responding patients. • Optimal treatment duration for patients with stable disease remains unknown. [ABSTRACT FROM AUTHOR]

Patients with degenerative cervical myelopathy (DCM) often present with atypical symptoms such as vertigo, headache, palpitations, tinnitus, blurred vision, memory loss, and abdominal discomfort. This study aims to investigate the relationship between atypical symptoms of DCM and the segments of spinal cord compression. The 166 DCM patients with atypical symptoms admitted to our institution from 2019 to 2020 were divided into vertigo, headache, blurred vision, tinnitus, and palpitations groups according to their atypical symptoms, while the typical group was 214 DCM patients with typical symptoms only. Differences in segments of compression were compared among the groups. Results of more than 1-year of follow-up were further summarized for nonsurgical and surgical treatment of DCM patients with atypical symptoms. The incidence of vertigo, headache, blurred vision, tinnitus, and palpitations of all DCM patients was 37%, 18%, 15%, 11%, and 11%, respectively. Compared with the typical group, patients in the blurred vision and tinnitus group were older (P < 0.05) and the incidence of spinal cord compression at C3-5 in the vertigo group, C4-5 in the headache group, and C6-7 in the palpitation group was higher (P < 0.05). The scores of vertigo, headache, and palpitations decreased after surgical decompression (P < 0.05), whereas only vertigo and headache scores decreased after nonsurgical treatment (P < 0.05). Atypical symptoms were common in patients with DCM, and the segments of spinal cord compression might be associated with specific atypical symptoms. Surgical treatment is effective in relieving some of the atypical symptoms. [ABSTRACT FROM AUTHOR]

Simple Summary: It is not known if surgery, radiation treatment (RT) or other types of locolregional treatment (LRT) may be beneficial for patients with metastatic gastrointestinal stromal tumor (mGIST) in addition to systemic treatment. Our study aims to address this question by analyzing a cohort of 127 mGIST patients in British Columbia over a decade (from January 2008 to December 2017). We showed that mGIST patients who underwent surgery and LRT seemed to have better survival when compared to patients who did not undergo surgery and LRT. However, this treatment strategy should only be considered in patients with limited volume metastatic disease or oligoprogression while the rest of the disease is well controlled with systemic treatment. In addition, RT can offer palliative benefits such as pain relief and bleeding control. Our study, consistent with other retrospective studies, supports LRT consideration in selected mGIST patients within a multidisciplinary setting. This approach is not considered as a "standard of care" due to lack of prospective clinical trials but may improve clinical outcome for some mGIST patients. Introduction: The role of surgery and non-surgical locoregional treatments (LRT) such as radiation therapy (RT) and local ablation techniques in patients with metastatic gastrointestinal stromal tumor (GIST) is unclear. This study examines LRT practice patterns in metastatic GIST and their clinical outcomes in British Columbia (BC). Methods: Patients diagnosed with either recurrent or de novo metastatic GIST from January 2008 to December 2017 were identified. Clinical characteristics and outcomes were analyzed in patients who underwent LRT, including surgical resection of the primary tumor or metastectomy, RT, or other local ablative procedures. Results: 127 patients were identified: 52 (41%) had de novo metastasis and 75 (59%) had recurrent metastasis. Median age was 67 (23–90 years), 58.2% were male, primary site was 33.1% stomach, 40.2% small intestine, 11% rectum/pelvis, and 15.7% others. 37 (29.1%) of patients received palliative surgery, the majority of which had either primary tumor removal only (43.3%) or both primary tumor removal and metastectomy (35.1%). A minority of patients underwent metastectomy only (21.6%). A total of 12 (9.5%) patients received palliative RT to metastatic sites only (58.3%) or primary tumors only (41.7%), mostly for symptomatic control (n = 9). A few patients (n = 3) received local ablation for liver metastatic deposits with 1 patient receiving microwave ablation (MWA) and 2 receiving radiofrequency ablation (RFA). Most patients (n = 120, 94.5%) received some type of systemic treatment. It is notable that prolonged progression free survival (PFS) was observed for the majority of patients who underwent surgery in the metastatic setting with a median PFS of 20.5 (95% confidence interval (CI): 14.29–40.74) months. In addition, significantly higher median overall survival (mOS) was observed in patients who underwent surgery (97.15 months; 95% CI: 77.7-not reached) and LRT (78.98 months; 95% CI: 65.58-not reached) versus no surgery (45.37 months; 95% CI: 38.7–64.69) and no LRT (45.27 months; 95% CI: 33.25–58.66). Almost all patients (8 out of 9) achieved symptomatic improvement after palliative RT. All 3 patients achieved partial response and 2 out of 3 patients had relatively durable responses of 1 year or more after local ablation. Discussion: This study is among the first to systematically examine the use of various LRT in metastatic GIST management. Integration of LRT with systemic treatments may potentially provide promising durable response and prolonged survival for highly selected metastatic GIST patients with low volume disease, limited progression and otherwise well controlled on systemic treatments. These observations, consistent with others, add to the growing evidence that supports the judicious use of LRT in combination with systemic treatments to further optimize the care of metastatic GIST patients. [ABSTRACT FROM AUTHOR]

Malignant gastrointestinal neuroectodermal tumor (GNET) is an ultra-rare soft tissue sarcoma, therefore often misdiagnosed and has no available standard treatment. Here, we report 3 cases of metastatic GNET with variable clinical courses. Our small case series as well as extensive literature review, further support that GNET is a spectrum of diseases with variable inherent biology and prognosis. Surgical management in the setting of recurrent/metastatic disease may be appropriate for GNET with indolent nature. Response to systemic treatments including chemotherapy and targeted treatments is variable, likely related to heterogenous biology as well. Furthermore, we retrospectively identified 20 additional GNET cases from Foundation Medicine's genomic database and expanded on their clinicopathological and genomic features. Comprehensive genomic profiling (CGP) with DNA and RNA sequencing of this cohort, in the course of clinical care, demonstrated recurrent EWSR1 chromosomal rearrangements and a sparsity of additional recurrent or driver genomic alterations. All cases had low tumor mutational burden (TMB) and were microsatellite stable. [ABSTRACT FROM AUTHOR]

Genetic studies in model organisms have shown that programmed cell death (apoptosis) plays a significant role during development, where a deficiency in apoptosis results in severe and diverse diseases. Dysregulation of apoptosis also contributes to a variety of human diseases, such as cancer and autoimmune diseases. ING family proteins (ING1-ING5) are involved in many cellular processes, and appear to play a significant role in apoptosis. Loss or downregulation of ING protein function is frequently observed in different tumour types, many of which are resistant to apoptosis, thus warranting their classification as type II tumour suppressors. Several different in vitro and in vivo models have explored the role of ING proteins in regulating apoptosis. In this review, we discuss the progress that has been made in understanding ING protein function in apoptosis using in vitro studies and Mus musculus, Xenopus laevis, and Caenorhabditis elegans experimental models, with an emphasis on ING1 and ING3. Des études génétiques chez des organismes modèles ont démontré que la mort cellulaire programmée (apoptose) joue un rôle significatif lors du développement, où une déficience de l’apoptose résulte en des maladies sévères et variées. Le dérèglement de l’apoptose contribue aussi à une variété de maladies chez l’humain comme le cancer et les maladies auto-immunes. Les protéines membres de la famille de ING (ING1-ING5) sont impliquées dans plusieurs processus cellulaires et semblent jouer un rôle important dans l’apoptose. La perte ou la diminution de la fonction des protéines ING est aussi fréquemment observée dans différents types de tumeurs, la plupart d’entre elles étant résistantes à l’apoptose, ce qui permet de classer ces protéines chez les suppresseurs de tumeurs de type II. Plusieurs modèles in vitro et in vivo ont servi à explorer le rôle des protéines ING dans la régulation de l’apoptose. Dans cet article de synthèse, nous discutons des progrès accomplis dans la compréhension de la fonction des ING dans l’apoptose dans des modèles expérimentaux in vitro, chez Mus musculus, Xenopus laevi et Caenorhabditis elegans, en mettant l’emphase sur ING1 et ING3. [ABSTRACT FROM AUTHOR]

Abstract: The INhibitor of Growth (ING) tumor suppressor gene family is important in regulating cell fate and reads the epigenetic code by interacting specifically with methylated histone H3. Several transcript variants are expressed from the five ING genes but nomenclature for these variants are not consistent in the literature, and very little is known regarding transcript variant expression in normal human tissues and during development. Here we propose a standardized nomenclature for human ING gene family transcript variants and present an expression analysis using real-time quantitative PCR. We establish the steady-state levels of eleven human ING mRNA transcript variants across several fetal, adult, and tumor tissues as well as in cancer-derived cell lines. Consistent with their roles as type II tumor suppressors, we find up to 10,000-fold reduction in many transcript variants in a subset of neoplastic cells. We also find considerable variation in expression levels in different tissues, with up to 1 million-fold higher expression of some ING transcripts in adult, compared to fetal counterparts, particularly in the brain cerebral cortex. These results show differential expression of specific subsets of ING1–5 transcript variants in tissues that may influence the degree to which these variants contribute to epigenetic regulation in cancer and development. [Copyright &y& Elsevier]

Layered double hydroxides (LDHs) have been widely used as an important subset of solid base catalysts. However, developing low-cost, small-sized LDH nanoparticles with enhanced surface catalytic sites remains a challenge. In this work, silica aerogel (SA)-supported, small-sized Mg-Al LDH nanosheets were successfully prepared by one-pot coprecipitation of Mg and Al ions in an alkaline suspension of crushed silica aerogel. The supported LDH nanosheets were uniformly dispersed in the SA substrate with the smallest average radial diameter of 19.2 nm and the thinnest average thickness of 3.2 nm, both dimensions being significantly less than those of the vast majority of LDH nanoparticles reported. The SA/LDH composites also showed large pore volume (up to 1.3 cm3·g) and pore diameter (>9 nm), and therefore allow efficient access of reactants to the edge catalytic sites of LDH nanosheets. In a base-catalyzed Henry reaction of benzaldehyde with nitromethane, the SA/LDH catalysts showed high reactant conversions and favorable stability in 6 successive cycles of reactions. The low cost of the SA carrier and LDH precursors, easy preparation method, and excellent catalytic properties make these SA/LDH composites a competitive example of solid-base catalysts. [ABSTRACT FROM AUTHOR]

Anti-microtubule therapy represents one of the most strategic cancer therapeutics. Tublin inhibitor such as paclitaxel (PTX) is well known to disturb the dynamic nature of microtubules, being considered as the first-line drug for various malignancies. However, PTX does not show favorable clinical outcomes due to serious systemic toxicities and low selectivity. The development of PTX delivery systems and combinational therapies has been conducted to enhance PTX efficacy with poorly defined mechanisms. Herein, we introduced a reactive oxygen species producible composite liposome based on a new photosensitizer sinoporphyrin sodium (DVDMS) to enhance the therapeutic effect of PTX through photochemical stimulation, and more importantly, the pivotal molecular regulation mechanisms were specifically explored. Compared with DVDMS-liposome (DL) or PTX-liposome (PL), the composite liposome DVDMS-PTX-liposome (PDL) exhibited a superior anti-tumor advantage following laser irradiation against MCF-7 breast cancer. The localized PTX release after PDL administration greatly decreased the drug dosage and laser power required, leading to much higher safety and lower costs. In vitro, the combined treatment significantly suppressed cell viability and potentiated cell apoptosis. The apoptotic central regulator Mcl-1 as a favorable target, was evaluated in association with photochemically enhanced sensitivity to anti-tubulin chemotherapeutics. Phosphorylation of Mcl-1 led to its direct degradation with the proteasome system, making it relatively unstable and potentiating cell death resulting from photochemical synergy via PDL plus laser irradiation. Further, a decrease in ATP production and glycolysis after PDL plus laser would prevent the possible energy-switch and apoptosis-escape by PTX alone treatment, thereby resulted in increased cell death in combinational therapy. Systemic administration of PDL followed by in vivo photochemotherapy achieved significantly improved therapeutic effects compared to either alone. And, the intrinsic fluorescence of DVDMS facilitated real-time imaging of PDL in tumors. Therefore, the present strategy with details at the molecular regulation could be a promising platform for antitublin chemotherapeutics. [ABSTRACT FROM AUTHOR]

The main objective of this study was to evaluate the efficacy of administration of doxorubicin (DOX) in combination with protoporphyrin IX (PpIX)-assisted low-level therapeutic ultrasound (US) in K562/DOX cells as a potential strategy in cancer therapy. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine the cytotoxicity of different treatments. Apoptosis was analyzed using annexin V-PE/7-amino-actinomycin D staining. Changes in DNA fragmentation, intracellular reactive oxygen species production, cellular membrane permeability, P-glycoprotein expression and DOX uptake were analyzed with flow cytometry. Under optimal conditions, PpIX-US significantly aggravated DOX-induced K562/DOX cell death, compared with either monotherapy. Synergistic potentiation of DNA damage, generation of reactive oxygen species and P-glycoprotein inhibition were observed. Plasma membrane integrity changed slightly after US exposure, and DOX uptake was notably improved after PpIX-US exposure. The results indicate that PpIX-US could increase the susceptibility of tumors to antineoplastic drugs, suggesting a clinical potential method for sonodynamic therapy-mediated tumor chemotherapy. [ABSTRACT FROM AUTHOR]

Sono-Photodynamic therapy (SPDT), a new modality for cancer treatment, is aimed at enhancing anticancer effects by the combination of sonodynamic therapy (SDT) and photodynamic therapy (PDT). In this study, we investigated the antitumor effect and possible mechanisms of Chlorin e6 (Ce6) mediated SPDT (Ce6-SPDT) on breast cancer both in vitro and in vivo. MTT assay revealed that the combined therapy markedly enhanced cell viability loss of breast cancer cell lines (MDA-MB-231, MCF-7 and 4T1) compared with SDT and PDT alone. Propidium iodide/hoechst33342 double staining reflected that 4T1 cells with apoptotic morphological characteristics were significantly increased in groups given combined therapy. Besides, the combined therapy caused obvious mitochondrial membrane potential (MMP) loss at early 1 h post SPDT treatment. The generation of intracellular reactive oxygen species (ROS) detected by flow cytometry was greatly increased in 4T1 cells treated with the combination therapy, and the loss of cell viability and MMP could be effectively rescued by pre-treatment with the ROS scavenger N-acetylcysteine (NAC). Further, Ce6-SPDT markedly inhibited the tumor growth (volume and weight) and lung metastasis in 4T1 tumor-bearing mice, but had no effect on the body weight. Hematoxylin and eosin staining revealed obvious tissue destruction with large spaces in the Ce6-SPDT groups, and TUNEL staining indicated tumor cell apoptosis after treatment. Immunohistochemistry analysis showed that the expression level of VEGF and MMP were significantly decreased in the combined groups. These results indicated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, loss of MMP and generation of ROS might be involved. In addition, Ce6-mediated SPDT significantly inhibited tumor growth and metastasis in mouse breast cancer 4T1 xenograft model, in which MMP-9 and VEGF may play a crucial role. [ABSTRACT FROM AUTHOR]

Highlights: [•] Migration inhibition of 4T1 cells was greatly enhanced by Chlorin e6-mediated Sono-Photodynamic therapy (SPDT). [•] Ce6-SPDT induced apoptosis of 4T1 cells, which may be mitochondria-dependent. [•] Autophagy was involved in Ce6-SPDT in 4T1 cells. [ABSTRACT FROM AUTHOR]

Purpose: The present study aims to investigate the antitumor effect and possible mechanisms of chlorin e6 (Ce6)-mediated sono-photodynamic therapy (Ce6-SPDT) on murine 4T1 mammary cancer cells in vitro. Materials: Cellular uptake and intracellular distribution of Ce6 in 4T1 cells were detected by flow cytometry and confocal microscope. Cells after loading with 1 μg/mL Ce6 were exposed to ultrasound at 1.0 MHz for up to 1 minute with an intensity of 0.36 W/cm2 and laser light with total radiation dose of 1.2 J/cm2. Cell viability and clonogenicity were determined by MTT assay and colony formation assay. Apoptosis was analyzed by DAPI staining, Western blots were used to detect the activity of Caspase-3. DNA damage, mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) of 4T1 cells were also evaluated by flow cytometry. FD500 was employed to detect changes of membrane permeability after ultrasound. Results: Ce6 rapidly entered 4T1 cells within 4 hours after it has been added and displayed a mitochondria-localization pattern. Compared with sonodynamic therapy (SDT) and photodynamic therapy (PDT) alone, the combined SPDT treatment further enhanced cell viability loss, DNA damage, and clonogenicity inhibition. DAPI staining and western blots analysis reflected that cells with apoptotic morphological characteristics and the activity of Caspase-3 were apparently increased in the combined group. Besides, SPDT caused obvious MMP loss and intracellular ROS generation at early 1 hour post treatment. Interestingly, the SPDT induced cell viability loss and cell apoptosis was greatly inhibited by pre-treatment with ROS scavenger N-acetylcysteine and Caspase inhibitor z-VAD-fmk. FD500 detection showed that ultrasound enhanced cell membrane permeability, implying much higher uptake of Ce6 might be involved in PDT therapy by pre-ultrasound treatment. Conclusions: The findings demonstrated that Ce6-mediated SPDT enhanced the antitumor efficacy on 4T1 cells compared with SDT and PDT alone, a Caspase-dependent apoptosis and loss of MMP, generation of ROS may be involved. [ABSTRACT FROM AUTHOR]

The ING family of tumor suppressor proteins affects cell growth, apoptosis and response to DNA damage by modulating chromatin structure through association with different HAT and HDAC complexes. The major splicing isoforms of the ING1 locus are ING1a and INGlb. While INGlb plays a role in inducing apoptosis, the function of ING1a is currently unknown. Here we show that alternative splicing of the ING1 message alters the INGla:INGlb ratio by ~30-fold in senescent compared to low passage primary fibroblasts. INGla antagonizes INGlb function in apoptosis, induces the formation of structures resembling senescence-associated heterochromatic foci containing heterochromatin protein 1 gamma, the accumulation of senescence-associated β-galactosidase activity and promotes senescent cell morphology and cell cycle arrest. Phenotypic effects may result from differential effects on gene expression since ING1a increases levels of both retinoblastoma and the p16 cyclin-dependent kinase inhibitor and ING1a and ING1b have opposite effects on the expression of proliferating nuclear cell antigen (PCNA), which is required for cell growth. Gene expression appears to be altered by targeting of HDAC complexes to gene promoters since INGla associates with several-fold higher levels of HDAC1 in senescent, compared to replication-competent cells and ING1 is found on the PCNA promoter by chromatin immunoprecipitation analysis. These data demonstrate a novel role for the ING1 proteins in differentially regulating senescence-associated chromatin remodeling vs. apoptosis and support the idea that altered ratios of the ING1 splicing isoforms may contribute to establishing the senescent phenotype through HDAC and HAT complex-mediated effects on chromatin structure. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a clinical treatment for cancer or non-neoplastic diseases, and the photosensitizers (PSs) are crucial for PDT efficiency. The commonly used chemical PSs, generally produce ROS through the type II reaction that highly relies on the local oxygen concentration. However, the hypoxic tumor microenvironment and unavoidable dark toxicity of PSs greatly restrain the wide application of PDT. The genetically encoded PSs, unlike chemical PSs, can be modified using genetic engineering techniques and targeted to unique cellular compartments, even within a single cell. KillerRed, as a dimeric red fluorescent protein, can be activated by visible light or upconversion luminescence to execute the Type I reaction of PDT, which does not need too much oxygen and surely attract the researchers' focus. In particular, nanotechnology provides new opportunities for various modifications of KillerRed and versatile delivery strategies. This review more comprehensively outlines the applications of KillerRed, highlighting the fascinating features of KillerRed genes and proteins in the photodynamic systems. Furthermore, the advantages and defects of KillerRed are also discussed, either alone or in combination with other therapies. These overviews may facilitate understanding KillerRed progress in PDT and suggest some emerging potentials to circumvent challenges to improve the efficiency and accuracy of PDT. [ABSTRACT FROM AUTHOR]