Arsenic trioxide used in endodontic treatments has been shown to cause severe damages to surrounding bone and periodontal tissues. This report describes a case of alveolar osteomyelitis triggered by arsenic trioxide pulp devitalization and associated with mycotic infestation. Following clinical and radiological examinations, the concerned tooth was extracted, bone sequestrum was removed and granulation tissue was debrided. Histopathological biopsy examination, stained with hematoxylin/eosin, Grocott's silver methenamine and periodic acid-Schiff, confirmed the diagnosis of chemical osteomyelitis associated with fungal infestation. Six months postoperatively, normal bone healing was observed.

Hepatocellular carcinoma (HCC) has a poor response to most available systemic therapies due to intrinsic or acquired resistance to apoptosis. Ferroptosis-based therapy is expected to circumvent those limitations. Therefore, the rational design of ferroptosis-based therapies with targeted delivery of ferroptosis inducers for HCC is in need. In this study, we found that arsenic trioxide (ATO) can efficiently induce ferroptosis in HCC cells, and this effect could be reversed by the iron chelator deferoxamine. On this basis, a drug delivery system was constructed to enhance the therapeutic efficacy of ATO by camouflaging ATO-loaded magnetic nanoparticles (Fe3O4) with HCC cell membranes, termed AFN@CM. After AFN@CM treatment, glutathione peroxidase 4 was strongly inhibited and intracellular lipid peroxide species were significantly increased in HCC cells. In addition, enhanced ferroptosis and tumor suppression were observed both in vitro and in vivo. The bio-safety of AFN@CM was also demonstrated by the in vivo toxicity evaluation. In addition, benefiting from the cell membrane coating, AFN@CM showed enhanced accumulation at tumor sites and achieved continuous tumor elimination in the mouse model. In conclusion, AFN@CM exhibited satisfactory therapeutic efficacy in the treatment of HCC and provided a desirable ferroptosis-based strategy for safe and reliable HCC therapeutics.

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) that is characterized by the PML::RARA fusion or, more rarely, a variant RARA translocation. While APL can be clinically suspected, diagnosis of APL requires genetic confirmation. Targeted therapy such as all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has dramatically improved the prognosis of APL patients, but this is dependent on timely genetic testing as different fusions and/or mutations can affect therapeutic outcomes. Here we report three APL cases with various genetic aberrations: cryptic PML::RARA fusion, variant RARA rearrangement, and typical PML::RARA fusion with co-existing FLT3-ITD mutation. They serve to illustrate the utility of integrating genetic testing, using chromosome analysis, fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS) in providing a detailed understanding of the genetic alterations underlying each patient's disease.

In this work, multifunctional thiolated chitosan derivatives (DCA-CS-PEG-FA-NAC) were synthesized, and arsenic trioxide (ATO) was loaded onto the derivatives through glutathione (GSH)-sensitive AsIII-S bonds, and stable CS-ATO nanodrugs were prepared by simple self-assembly method. By adjusting the thiol substitution degree of CS, the drug loading capacity of the nanodrugs was significantly improved, which could reach 20 ATO per CS molecule (DCA10.7-CS-PEG3.1-FA-NAC20.2-ATO). In vitro release studies obviously showed the low leakage of ATO under physiological conditions while over 95 % ATO was released after 24 h under GSH. In vitro and in vivo investigations demonstrated that the DCA10.7-CS-PEG3.1-FA-NAC20.2-ATO nanodrug could significantly enhance the tumor intracellular accumulation of ATO, reduce the toxic and side effects of ATO on healthy organs, and improve the therapeutic effect of ATO on the HepG2 mice tumor model (tumor inhibition rate was as high as 86.4 %), indicating the potential application of ATO in clinical treatment of liver cancer.

Glioblastoma multiforme (GBM) is the most malignant brain tumor with high mortality. Knowledge of the stemness concept has developed recently, giving rising to a novel hallmark with therapeutic potential that can help in management of GBM recurrence and prognosis. However, limited blood-brain barrier (BBB) penetration, non-discriminatory distribution, and deficiency of diagnosis remain three major obstacles need to be overcome for further facilitating therapeutic effects. Herein, D4F and α-Melittin (a-Mel) are co-assembled to construct bio-fabricated nanoplatforms, which endowed with inherent BBB permeability, precise tumor accumulation, deep penetration, and immune activation. After carrying arsenic trioxide (ATO) and manganese dichloride (MnCl2), these elaborated nanodrugs, Mel-LNPs/MnAs, gather in tumor foci by natural pathways and respond to microenvironment to synchronously release Mn2+ and As3+, achieving real-time navigating-diagnosis and tumor cell proliferation inhibition. Through down regulating CD44 and CD133 expression, the GBM stemness was suppressed to overcome its high recurrence, invasion, and chemoresistance. After being combined with temozolomide (TMZ), the survival rate of GBM-bearing mice is significantly enhanced, and the rate of recurrence is powerfully limited. Collectively, this tumor-specific actuating multi-modality nanotheranostics provide a promising candidate for clinical application with high security.

Kirsten rat sarcoma (KRAS) protein is an essential contributor to the development of pancreatic ductal adenocarcinoma (PDAC). KRAS G12D and G12V mutant tumours are significant challenges in cancer therapy due to high resistance to the treatment.

Urbanisation and industrialisation are on the rise all over the world. Environmental contaminants such as potentially toxic elements (PTEs) are directly linked with both phenomena. Two PTEs that raise greatest concern are arsenic (As) and lead (Pb) as soil and drinking water contaminants, whether they are naturally occurring or the consequence of human activities. Both elements are potential carcinogens. This paper reviews the mechanisms by which As and Pb impair metabolic processes and cause genetic damage in humans. Despite efforts to ban or limit their use, due to high persistence both continue to pose a risk to human health, which justifies the need for further toxicological research.

It has been found that arsenic trioxide (ATO) is effective in treating acute promyelocytic leukemia (APL). However, long QT syndrome was reported in patients receiving therapy using ATO, which even led to sudden cardiac death. The underlying mechanisms of ATO-induced cardiotoxicity have been investigated in some biological experiments, showing that ATO affects human ether-à-go-go-related gene (hERG) channels, coding rapid delayed rectifier potassium current (I Kr), as well as L-type calcium (I CaL) channels. Nevertheless, the mechanism by which these channel reconstitutions induced the arrhythmia in ventricular tissue remains unsolved. In this study, a mathematical model was developed to simulate the effect of ATO on ventricular electrical excitation at cellular and tissue levels by considering ATO's effects on I Kr and I CaL . The ATO-dose-dependent pore block model was incorporated into the I Kr model, and the enhanced degree of ATO to I CaL was based on experimental data. Simulation results indicated that ATO extended the action potential duration of three types of ventricular myocytes (VMs), including endocardial cells (ENDO), midmyocardial cells (MCELL), and epicardial cells (EPI), and exacerbated the heterogeneity among them. ATO could also induce alternans in all three kinds of VMs. In a cable model of the intramural ventricular strand, the effects of ATO are reflected in a prolonged QT interval of simulated pseudo-ECG and a wide vulnerable window, thus increasing the possibility of spiral wave formation in ventricular tissue. In addition to showing that ATO prolonged QT, we revealed that the heterogeneity caused by ATO is also an essential hazard factor. Based on this, a pharmacological intervention of ATO toxicity by resveratrol was undertaken. This study provides a further understanding of ATO-induced cardiotoxicity, which may help to improve the treatment for APL patients.

Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization.

Given the lack of advances in Oral Squamous Cell Carcinoma (OSCC) therapy in recent years, pharmacological strategies to block OSCC-related signaling pathways have gained prominence. The present study aimed to evaluate the therapeutic potential of Arsenic Trioxide (ATO) concerning its antitumoral effects and the inhibition of the Hedgehog (HH) pathway in OSCC. Initially, ATO cytotoxicity was assessed in a panel of cell lines. Cell viability, cell cycle, death patterns, and cell morphology were analyzed, as well as the effect of ATO on the expression of HH pathway components. After the cytotoxic assay, HSC3 cells were chosen for all in vitro assays. ATO increased apoptotic cell death and nuclear fragmentation in the sub-G1 cell cycle phase and promoted changes in cell morphology. In addition, the reduced expression of GLI1 indicated that ATO inhibits HH activity. The present study provides evidence of ATO as an effective cytotoxic drug for oral cancer treatment in vitro.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high-risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate- and high-risk disease received a further 2 years of maintenance with ATRA, 6-mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow-up. The mean (SD) estimated 5-year event-free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5-year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting.

Although arsenic is an environmental toxicant, arsenic trioxide (ATO) is used to treat acute promyelocytic leukemia (APL) with anticancer effects. Studies have demonstrated oral cancer is in the top 10 cancers in Taiwan. High rate of oral cancers is linked to various behaviors, such as excessive alcohol consumption and tobacco use. Similarly, betel chewing is a strong risk factor in oral cancer. In the present study, oral squamous carcinoma OC3 cells were investigated with the treatments of sodium arsenite (NaAsO2) and dimethylarsenic acid (DMA), respectively, to examine if arsenic compounds have anti‑cancer efforts. It was found that 1 µM NaAsO2 and 1 mM DMA for 24 h induced rounded contours with membrane blebbing phenomena in OC3 cells, revealing cell apoptotic characteristics. In addition, NaAsO2 (10‑100 µM) and DMA (1‑100 mM) significantly decreased OC3 cell survival. In cell cycle regulation detected by flow cytometry, NaAsO2 and DMA significantly augmented percentage of subG1 and G2/M phases in OC3 cells, respectively. Annexin V/PI double staining assay was further used to confirm NaAsO2 and DMA did induce OC3 cell apoptosis. In mechanism investigation, western blotting assay was applied and the results showed that NaAsO2 and DMA significantly induced phosphorylation of JNK, ERK1/2 and p38 and then the cleavages of caspase‑8, ‑9, ‑3 and poly ADP‑ribose polymerase (PARP) in OC3 cells, dynamically. In conclusion, NaAsO2 and DMA activated MAPK pathways and then apoptotic pathways to induce OC3 oral cancer cell apoptosis.

Intracranial hemorrhage (ICH) is a major cause of early death (ED) and leads to poor prognosis in acute promyelocytic leukemia (APL). We retrospectively described 27 unselected APL patients who experienced early ICH. The ED rate was 37%. The 3-year overall survival (OS) rate was 45.4%, while the 3-year OS rate of patients who survived through induction therapy was 87.5%. No patient experienced central nervous system leukemia (CNSL). Concurrent differentiation syndrome, white blood cell count, prothrombin time and D-dimer were related to death. Although the ED rate among APL patients with early ICH was high, patients with early ICH had a favorable outcome after surviving through induction therapy. CNSL was rare despite a history of ICH during induction therapy. Compared with APL patients without ICH, it seems unnecessary to administer additional measures to prevent CNSL for this subpopulation in the era of all-trans retinoic acid and arsenic trioxide, but this needs further validation in prospective trials.

This account describes how orally administered Arsenic-trioxide (ATO) therapy influences the epidemiology of acute promyelocytic leukaemia (APL), and how the experience that ensued may expand the indications for oral ATO as a treatment for diseases/disorders other than APL. Over the last two decades, experience with APL patients in Hong Kong treated with an oral regimen comprising ATO, all-trans retinoic acid (ATRA), and ascorbic acid (also known as "AAA") has confirmed a dramatic improvement in overall survival. Over that period, there has been an estimated 60-fold increase in the prevalence of APL (proportion of surviving APL patients in the population on December 31 including those deemed to be 'cured'). In contrast to regimens entailing intravenous (IV) ATO, the consequential therapeutic benefits of using oral ATO have been achieved with much less patient inconvenience and quality of life disruption, reduced burdens on health care facilities (hospitalisations and staff involvement), and much enhanced affordability (retail drug & other cost reductions). Numerous experimental and a few clinical studies suggest that ATO may also have a therapeutic role in many other diseases/disorders. Several such diseases (e.g. autoimmune disorders & idiopathic pulmonary fibrosis) are far more prevalent than APL, which means that very large numbers of patients may potentially benefit from ATO treatment, even if its efficacy is limited to selected populations with these diseases. The known safety of oral ATO and its advantages over repeated long-term IV delivery suggests that this route be used in future clinical studies of its possible role in treating such patients. If the clinical utility of oral ATO treatment is validated for patients enduring any such non-APL diseases, very large numbers of patients may stand to benefit.

Inorganic arsenic is highly toxic, widely distributed in the human environment and may result in multisystem diseases and several types of cancers. The BCL-2-interacting mediator of cell death protein (BIM) is a key modulator of the intrinsic apoptosis pathway. Interestingly, in the present study, we found that arsenic trioxide (As2O3) decreased BIMEL levels in human bronchial epithelial cell line BEAS-2B and increased BIMEL levels in human lung carcinoma cell line A549 and mouse Sertoli cell line TM4. Mechanismly, the 26S proteasome inhibitors MG132 and bortezomib could effectively inhibit BIMEL degradation induced by As2O3 in BEAS-2B cells. As2O3 activated extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, but only the ERK1/2 MAPK inhibitor PD98059 blocked BIMEL degradation induced by As2O3. Furthermore, As2O3 induced-phosphorylation of BIMEL at multiple sites was inhibited by ERK1/2 MAPK inhibitor PD98059. Inhibition of As2O3-induced ERK1/2 MAPK phosphorylation increased the levels of BIMEL and cleaved-caspase-3 proteins and decreased BEAS-2B cell viability. As2O3 also markedly mitigated tunicamycin-induced apoptosis of BEAS-2B cells by increasing ERK1/2 phosphorylation and BIMEL degradation. Our results suggest that As2O3-induced activation of the ERK1/2 MAPK pathway increases phosphorylation of BIMEL and promotes BIMEL degradation, thereby alleviating the role of apoptosis in As2O3-induced cell death. This study provides new insights into how to maintain the survival of BEAS-2B cells before malignant transformation induced by high doses of As2O3.

Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) represents an advanced stage of the disease and frequently shows resistance to these current treatments, including platinum chemotherapy, cetuximab plus chemotherapy, and checkpoint inhibitors. EGFR overexpression and TP53 mutation are the most frequent genetic changes in patients with HNSCC. On the basis of this genetic feature, we proposed a combinatorial treatment using the EGFR tyrosine kinase inhibitor osimertinib (AZD) and arsenic trioxide (ATO) for compassionate use. The patient obtained treatment response and progression-free survival for about six months. In vitro mechanical verifications showed that ATO and AZD combination (ATO/AZD) significantly increased intracellular ROS levels and DNA damage. Additionally, ATO/AZD decreases the expression and activity of breast cancer type 1 susceptibility protein (BRCA1) and polo-like kinase 1 (PLK1), thereby impairing Rad51 recruitment to DNA double-strand lesion for repair and may ultimately cause tumor cell death. In conclusion, this study provides a concrete experience and an alternate strategy of ATO/AZD therapy for patients with R/M HNSCC.

This discourse attempts to capture a few important dimensions of gut physiology like microbial homeostasis, short chain fatty acid (SCFA) production, occludin expression, and gut permeability in post-natal life of mice those received arsenic only during pre-natal life. Adult Balb/c mice were fed with 4 ppm arsenic trioxide in drinking water during breeding and gestation. After the birth of the pups, the arsenic water was withdrawn and replaced with clean drinking water. The pups were allowed to grow for 28 days (pAs-mice) and age matched Balb/c mice which were never exposed to arsenic served as control The pAs-mice showed a striking reduction in Firmicutes to Bacteroidetes (F/B) ratio coupled with a decrease in tight junction protein, occludin resulting in an increase in gut permeability, increased infiltration of inflammatory cells in the colon and decrease in common SCFAs in which butyrate reduction was quite prominent in fecal samples as compared to normal control. The above phenotypes of pAs-mice were mostly reversed by supplementing 5% sodium butyrate (w/w) with food from 21st to 28th day. The ability of butyrate in enhancing occludin expression, in particular, was dissected further. As miR122 causes degradation of Occludin mRNA, we transiently overexpressed miR122 by injecting appropriate plasmids and showed reversal of butyrate effects in pAs-mice. Thus, pre-natal arsenic exposure orchestrates variety of effects by decreasing butyrate in pAs-mice leading to increased permeability due to reduced occludin expression. Our research adds a new dimension to our understanding that pre-natal arsenic exposure imprints in post-natal life while there was no further arsenic exposure.

Some forms of acute myelogenous leukemia (AML) share typical morphological and immunophenotypic features of acute promyelocytic leukemia (APL) but are negative for promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) fusion. These forms of AML are known as variant APL. Some variants of APL present with retinoic acid receptor beta (RARB) fused or rearranged with partner genes. RARB-positive APL is very rare, resistant to all-trans retinoic acid (ATRA), and associated with poor prognosis. Here, we reported one case with TBL1XR1-RARB positive APL, featured by early onset and no apparent bleeding tendency or coagulation dysfunction. This patient was resistant to ATRA and arsenic trioxide (ATO), but was good responsive to conventional chemotherapy for AML. The case report was followed by a literature review.

Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer. Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses, limited advances have been made in curative vaccines for virus-irrelevant malignancies. Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities. However, the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors. In this study, we identified arsenic trioxide (ATO) as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening. ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings. The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8+ T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules. Unexpectedly, following ATO-induced oxidative stress, multiple cell death pathways were activated, including autophagy, apoptosis, necroptosis, and ferroptosis. CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3, Mlkl, or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines. This therapeutic failure could be rescued by coadministration of danger molecule analogs. In addition, PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.

Granulomatosis with polyangiitis (GPA) is a rare disorder of unknown etiology, which is characterized by necrotizing granulomatous inflammation of the upper respiratory system and kidneys. Immunosuppressive treatment (cyclophosphamide or azathioprine with glucocorticoids) improved the outcome of GPA, however, latent comorbidity (cancers and hematologic malignancies) has become more prevalent in recent years. Here, we present a first case of the patient with GPA complicated by acute promyelocytic leukemia (APL) successfully treated with molecular-targeted therapy. A 77-year-old female was referred to our hospital for nasal obstruction, hearing loss, and fever. Otorhinolaryngological investigation revealed otitis media, and head computed tomography (CT) showed paranasal mucosal thickening with septal perforation. Chest CT showed cavitary granulomatous lesions in both lungs. Biopsy of the nasal mucosa revealed granulomatous lesions, and the patient was finally diagnosed with GPA. Oral administration of prednisolone 50 mg/day was initiated, and oral azathioprine (50 mg/day) was added. After 26 months of azathioprine initiation, pancytopenia developed and azathioprine was stopped. Then sudden elevated levels of blasts appeared in the hemogram (blasts 11%). She was diagnosed with APL via bone marrow examination which revealed plenty of faggot cells with Auer rods and chromosomal mutation. The patient was started on all-trans retinoic acid 60 mg/day following arsenic trioxide 7 mg/day in consideration of elderly onset. Complete remission was achieved and oral prednisolone was successfully reduced to 15 mg/day without a major relapse of GPA. Because GPA can be complicated by APL even during maintenance treatment using azathioprine, careful monitoring should be performed in such patients.