TRPC7 facilitates cell growth and migration by regulating intracellular Ca2+ mobilization in lung adenocarcinoma cells.

Transient receptor potential canonical 7 (TRPC7) has been reported to mediate aging-associated tumorigenesis, but the role of TRPC7 in cancer malignancy is still unclear. TRPC7 is associated with tumor size in patients with lung adenocarcinoma and the present study further evaluated the underlying mechanism of TRPC7 in the regulation of cancer progression. The clinicopathological role of TRPC7 was assessed using immunohistochemistry staining and the pathological mechanism of TRPC7 in lung adenocarcinoma cells was determined using cell cycle examination, invasion and calcium response assays, and immunoblot analysis. The results indicated that high TRPC7 expression was associated with a lower 5-year survival rate compared with low TRPC7 expression, which suggested that TRPC7 expression was inversely associated with overall survival in patients with lung adenocarcinoma. TRPC7 serves a pathological role by facilitating the enhancement of cell growth and migration with increased phosphorylation of Ca2+/calmodulin-dependent protein kinase II, AKT and ERK. TRPC7 knockdown in lung adenocarcinoma cells restrained cell cycle progression and cell migration by interrupting the TRPC7-mediated Ca2+ signaling-dependent AKT and MAPK signaling pathways. These findings demonstrated for the first time a role of oncogenic TRPC7 in the regulation of cancer malignancy and could provide a novel therapeutic molecular target for patients with lung adenocarcinoma.

Application of Supercharge End-to-Side (SETS) Obturator to Femoral Nerve Transfer in Electrical Injury-Induced Neuropathy to Improve Knee Extension.

Femoral nerve injuries are devastating injuries that lead to paralysis of the quadriceps muscles, weakening knee extension to prohibit ambulation. We report a devastating case of electrical injury-induced femoral neuropathy, where no apparent site of nerve disruption can be identified, thus inhibiting the traditional choices of nerve reconstruction such as nerve repair, grafting, or transfer. Concomitant spinal cord injury resulted in spastic myopathy of the antagonist muscles that further restricted knee extension. Our strategy was to perform (1) supercharge end-to-side technique (SETS) to augment the function of target muscles and (2) fractional tendon lengthening to release the spastic muscles. Dramatic postoperative improvement in passive and active range of motion highlights the effectiveness of this strategy to manage partial femoral nerve injuries.

Corrigendum: Compassionate use of ripretinib for patients with metastatic gastrointestinal stromal tumors: Taiwan and Hong Kong experience.

[This corrects the article DOI: 10.3389/fonc.2022.883399.].

Compassionate Use of Ripretinib for Patients With Metastatic Gastrointestinal Stromal Tumors: Taiwan and Hong Kong Experience.

Background: Ripretinib was recently approved for the fourth-line targeted therapy for advanced gastrointestinal stromal tumor (GIST) refractory to imatinib, sunitinib, and regorafenib based on the pivotal INVICTUS phase III study. The INVICTUS study demonstrated significantly improved median progression-free survival (PFS) of 6.3 months and an overall survival (OS) insignificant benefit of ripretinib of 15.1 months as compared with placebo in 85 patients with advanced metastatic GIST. However, treatment outcome for the Chinese population, including in Taiwan and Hong Kong, was lacking. Material and Method: A compassionate study regarding ripretinib use for patients with advanced/metastatic GIST was conducted from March 2020 to March 2021 to assess the treatment efficacy and safety in Taiwan and Hong Kong patients. Result: Twenty evaluable patients (16 men and 4 women) with heavily pretreated metastatic GIST receiving ripretinib from March 2020 to March 2021 were enrolled to evaluate the treatment outcome. The response and clinical benefit rates to ripretinib were 25% (5/20) and 60% (12/20), respectively. The median PFS and OS in this compassionate cohort receiving ripretinib were 6.1 months and not reachable, respectively. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. There were 14 out of 20 (70%) experiencing any grade adverse event (AE). Loss of hair is the most common grade I to II AE with an incidence of 55%. Grade III AEs included diarrhea, skin rash, and anemia with one patient (5%) for each AE. Conclusions: Late-line ripretinib use in pretreated Taiwan and Hong Kong patients with advanced GIST showed efficacy consistent with the INVICTUS study. Albumin less than 3.5 and disease progression after ripretinib use were the two independent unfavorable factors for PFS. Ripretinib is generally tolerable, with loss of hair being the most common AE.

Venous Size Discrepancy Is a Critical Factor When Using Superficial Temporal Vessels as Recipient Vessels for Free Flaps.

BACKGROUND: Superficial temporal vessels have been used successfully as recipient vessels for head and neck reconstruction. This study evaluates the impact of several treatment variables on flap failure and take-back rate when using these recipient vessels. METHODS: We conducted a retrospective study of all microsurgical reconstructions using superficial temporal vessels as recipient vessels in a period of 10 years. Variables collected included previous treatments (radiotherapy, chemotherapy, neck dissection, free flap reconstruction), type of flaps used (soft tissue, osteocutaneous), and vessel size discrepancy between donor and recipient vessels. RESULTS: A total of 132 patients were included in the study. The flap success rate was 98.5%. The take-back rate was 10.6%. The most frequent reason for take-back was venous congestion secondary to thrombosis. None of the studied variables was associated with flap failure. Reconstructions using osteocutaneous flaps and vein diameter discrepancy (ratio ≥ 2:1) had significantly higher take-back rates. CONCLUSION: Flaps with a significant size discrepancy between donor and recipient veins (ratio ≥ 2:1) and fibula flaps (compared with soft tissue flaps) were associated with a higher risk of take-back. It is crucial to minimize venous engorgement during flap harvest and anastomosis, and limit vein redundancy during flap in-setting.

Longitudinal alterations of the cisternal segment of trigeminal nerve and brain pain-matrix regions in patients with trigeminal neuralgia before and after treatment.

BACKGROUND: Trigeminal neuralgia (TN) is the most common type of chronic neuropathic facial pain, but the etiology and pathophysiological mechanisms after treatment are still not well understood. The purpose of this study was to investigate the longitudinal changes of the cisternal segment of the trigeminal nerve and brain pain-related regions in patients with TN before and after treatment using readout segmentation of long variable echo-train (RESOLVE) diffusion tensor imaging (DTI) and transverse relaxation (T2)-weighted sampling perfection with application-optimized contrast at different flip angle evolutions (T2-SPACE). METHODS: Twelve patients with TN and four healthy controls were enrolled in this study. All patients underwent assessment of the visual analog scale (VAS), and acquisition of RESOLVE DTI and T2-SPACE images before and at 1, 6, and 12 months after treatments. Regions-of-interest were placed on the bilateral anterior, middle, and posterior parts of the cisternal segment of the trigeminal nerve, the bilateral root entry zone (REZ), bilateral nuclear zone, and the center of pontocerebellar tracts, respectively. Voxel-based morphometry (VBM) analysis was conducted with T2-SPACE images, and gray matter volumes (GMV) were measured from brain pain-matrix regions. RESULTS: The results demonstrated that the VAS scores, the axial diffusivity of the middle part of the affected cisternal trigeminal nerve, the fractional anisotropy of the bilateral nuclear zones, and the mean diffusivity of the center of pontocerebellar tract significantly changed over time before and after treatment. The changes of GMV in the pain-matrix regions exhibited similar trends to the VAS before and after treatment. CONCLUSION: We conclude that magnetic resonance imaging with RESOLVE DTI and VBM with T2-SPACE images were helpful in the understanding of the pathophysiological mechanisms in patients with TN before and after treatment.

Nepenthes Ethyl Acetate Extract Provides Oxidative Stress-Dependent Anti-Leukemia Effects.

Several kinds of solvents have been applied to Nepenthes extractions exhibiting antioxidant and anticancer effects. However, they were rarely investigated for Nepenthes ethyl acetate extract (EANT), especially leukemia cells. The purpose of the present study was to evaluate the antioxidant properties and explore the antiproliferation impact and mechanism of EANT in leukemia cells. Five standard assays demonstrated that EANT exhibits antioxidant capability. In the cell line model, EANT dose-responsively inhibited cell viabilities of three leukemia cell lines (HL-60, K-562, and MOLT-4) based on 24 h MTS assays, which were reverted by pretreating oxidative stress and apoptosis inhibitors (N-acetylcysteine and Z-VAD-FMK). Due to similar sensitivities among the three cell lines, leukemia HL-60 cells were chosen for exploring antiproliferation mechanisms. EANT caused subG1 and G1 cumulations, triggered annexin V-detected apoptosis, activated apoptotic caspase 3/7 activity, and induced poly ADP-ribose polymerase expression. Moreover, reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane depolarization were generated by EANT, which was reverted by N-acetylcysteine. The antioxidant response to oxidative stress showed that EANT upregulated mRNA expressions for nuclear factor erythroid 2-like 2 (NFE2L2), catalase (CAT), thioredoxin (TXN), heme oxygenase 1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1) genes. Moreover, these oxidative stresses led to DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) and were alleviated by N-acetylcysteine. Taken together, EANT demonstrated oxidative stress-dependent anti-leukemia ability to HL-60 cells associated with apoptosis and DNA damage.

Pomegranate Extract (POMx) Induces Mitochondrial Dysfunction and Apoptosis of Oral Cancer Cells.

The anticancer effect of pomegranate polyphenolic extract POMx in oral cancer cells has rarely been explored, especially where its impact on mitochondrial functioning is concerned. Here, we attempt to evaluate the proliferation modulating function and mechanism of POMx against human oral cancer (Ca9-22, HSC-3, and OC-2) cells. POMx induced ATP depletion, subG1 accumulation, and annexin V/Western blotting-detected apoptosis in these three oral cancer cell lines but showed no toxicity to normal oral cell lines (HGF-1). POMx triggered mitochondrial membrane potential (MitoMP) disruption and mitochondrial superoxide (MitoSOX) generation associated with the differential downregulation of several antioxidant gene mRNA/protein expressions in oral cancer cells. POMx downregulated mitochondrial mass, mitochondrial DNA copy number, and mitochondrial biogenesis gene mRNA/protein expression in oral cancer cells. Moreover, POMx induced both PCR-based mitochondrial DNA damage and γH2AX-detected nuclear DNA damage in oral cancer cells. In conclusion, POMx provides antiproliferation and apoptosis of oral cancer cells through mechanisms of mitochondrial impairment.

Comparison of Antioxidant and Anticancer Properties of Soft Coral-Derived Sinularin and Dihydrosinularin.

Marine natural products are abundant resources for antioxidants, but the antioxidant property of the soft corals-derived sinularin and dihydrosinularin were unknown. This study aimed to assess antioxidant potential and antiproliferation effects of above compounds on cancer cells, and to investigate the possible relationships between them. Results show that sinularin and dihydrosinularin promptly reacted with 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), and hydroxyl (•OH), demonstrating a general radical scavenger activity. Sinularin and dihydrosinularin also show an induction for Fe+3-reduction and Fe+2-chelating capacity which both strengthen their antioxidant activities. Importantly, sinularin shows higher antioxidant properties than dihydrosinularin. Moreover, 24 h ATP assays show that sinularin leads to higher antiproliferation of breast, lung, and liver cancer cells than dihydrosinularin. Therefore, the differential antioxidant properties of sinularin and dihydrosinularin may contribute to their differential anti-proliferation of different cancer cells.

Large air pressure changes triggered by P-SV ground motion in a cave in northern Taiwan.

Acoustic-gravity waves are generally considered to be one of the major factors that drive changes of the total electron content in the ionosphere. However, causal mechanisms of couplings between sources in the lithosphere and responses in the atmosphere and the ionosphere are not fully understood, yet. A barometer in the cave of the SBCB station records an unusual phenomenon of larger amplitudes in air pressure changes inside than those at the Xinwu station (outside). Accordingly, the comparison between the recorded data at the SBCB and Xinwu station can drive investigations of potential sources of the unusual phenomenon. Analytical results of phase angle differences reveal that the air pressure outside the cave at the Xinwu station often leads air pressure changes inside at the SBCB station at relatively low frequency bands. In contrast, the larger pressure changes at frequencies > ~ 5 × 10-4 Hz inside the cave at the SBCB station lead smaller changes outside at the Xinwu station. To expose causal mechanisms of the unusual phenomenon, continuous seismic waveforms are further conducted for examination. When the horizontal and vertical ground velocities of ground vibrations yield a difference in the phase angle close to 90°, coherence values between the air pressure changes and ground vibrations become large. This suggests that the pressure-shear vertical ground vibrations can drive air pressure changes. Meanwhile, the results shed light on investigating the existence of acoustic waves near the Earth's surface using a partially confined space underground due to that the assumptions of the waves can propagate upward into the atmosphere driving changes in the ionosphere.

Physalis peruviana-Derived Physapruin A (PHA) Inhibits Breast Cancer Cell Proliferation and Induces Oxidative-Stress-Mediated Apoptosis and DNA Damage.

Breast cancer expresses clinically heterogeneous characteristics and requires multipurpose drug development for curing the different tumor subtypes. Many withanolides have been isolated from Physalis species showing anticancer effects, but the anticancer function of physapruin A (PHA) has rarely been investigated. In this study, the anticancer properties of PHA in breast cancer cells were examined by concentration and time-course experiments. In terms of cellular ATP content, PHA inhibited the proliferation of three kinds of breast cancer cells: MCF7 (estrogen receptor (ER)+, progesterone receptor (PR)+/-, human epidermal growth factor receptor 2 (HER2)-), SKBR3 (ER-/PR-/HER2+), and MDA-MB-231 (triple-negative). Moreover, PHA induced G2/M arrest in MCF7 and MDA-MB-231 cells. In terms of flow cytometry, PHA induced the generation of reactive oxygen species (ROS), the generation of mitochondrial superoxide, mitochondrial membrane potential depletion, and γH2AX-detected DNA damage in breast cancer MCF7 and MDA-MB-231 cells, which were suppressed by the ROS inhibitor N-acetylcysteine (NAC). In terms of flow cytometry and Western blotting, PHA induced apoptotic expression (annexin V, and intrinsic and extrinsic apoptotic signaling), which was suppressed by NAC and an apoptosis inhibitor (Z-VAD-FMK), in breast cancer cells. Therefore, PHA is a potential anti-breast-cancer natural product that modulates the oxidative-stress response, cell-cycle disturbance, apoptosis, and γH2AX-detected DNA damage.

Multi-Omics Data Analysis of Gene Expressions and Alterations, Cancer-Associated Fibroblast and Immune Infiltrations, Reveals the Onco-Immune Prognostic Relevance of STAT3/CDK2/4/6 in Human Malignancies.

Signal transducer and activator of transcription 3 (STAT3)/Cyclin-dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immunotherapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer-associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease-free survival of the cohorts. Moreover, genetic alterations in STAT3/CDK2/4/6 co-occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein-protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumorigenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it's associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco-immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow-up management of immunotherapy.

Low Dose Combined Treatment with Ultraviolet-C and Withaferin a Enhances Selective Killing of Oral Cancer Cells.

Withaferin A (WFA), a Withania somnifera-derived triterpenoid, is an anticancer natural product. The anticancer effect of nonionizing radiation such as ultraviolet-C (UVC) as well as the combined treatment of UVC and WFA is rarely investigated. Low dose UVC and/or WFA treatments (12 J/m2 and/or 1 µM) were chosen to evaluate antioral cancer cell line effects by examining cytotoxicity, cell cycle disruption, apoptosis induction, and DNA damage. For two cancer cell lines (Ca9-22 and HSC-3), single treatment (UVC or WFA) showed about 80% viability, while a combined treatment of UVC/WFA showed about 40% viability. In contrast, there was noncytotoxicity to normal oral cell lines (HGF-1). Compared to single treatment and control, low dose UVC/WFA shows high inductions of apoptosis in terms of flow cytometric detections for subG1, annexin V, pancaspase changes as well as Western blotting for detecting cleaved poly (ADP-ribose) polymerase (c-PARP) and caspase 3 (c-Cas 3) and luciferase assay for detecting Cas 3/7 activity. Low dose UVC/WFA also showed high inductions of oxidative stress and DNA damage in terms of flow cytometric detections of reactive oxygen species (ROS), mitochondrial superoxide (MitoSOX) generation, and membrane potential (MitoMP) destruction, γH2AX and 8-oxo-2'deoxyguanosine (8-oxodG) types of DNA damages. For comparison, low dose UVC/WFA show rare inductions of annexin V, Cas 3/7 activity, ROS, MitoSOX, and MitoMP changes to normal oral HGF-1 cells. Therefore, low dose UVC/WFA provides a novel selectively killing mechanism to oral cancer cells, suggesting that WFA is a UVC sensitizer to inhibit the proliferation of oral cancer cells.

NAD(P)H:quinone oxidoreductase 1 determines radiosensitivity of triple negative breast cancer cells and is controlled by long non-coding RNA NEAT1.

Radioresistant cells cause recurrence in patients with breast cancer after they undergo radiation therapy. The molecular mechanisms by which cancer cells obtain radioresistance should be understood to develop radiation-sensitizing agents. Results showed that the protein expression and activity of NAD(P)H:quinone oxidoreductase 1 (NQO1) were upregulated in radioresistant MDA-MB-231 triple-negative breast cancer (TNBC) cells. NQO1 knockdown inhibited the proliferation of NQO1 expressing Hs578t TNBC cells or the radioresistant MDA-MB-231 cells, whereas NOQ1 overexpression increased the survival of MDA-MB-231 cells, which lack of NQO1 expression originally, under irradiation. The cytotoxicity of ß-lapachone, an NQO1-dependent bioactivatable compound, was greater in radioresistant MDA-MB-231 cells than in parental cells. ß-lapachone displayed a radiosensitization effect on Hs578t or radioresistant MBDA-MB-231 cells. The expression of the long noncoding RNA NEAT1 positively regulated the NQO1 expression in radioresistant MDA-MB-231 cells at a translational level rather than at a transcription level. The inhibition of the NEAT1 expression through the CRISPR-Cas9 method increased the sensitivity of radioresistant MDA-MB-231 cells to radiation and decreased their proliferation, the activity of cancer stem cells, and the expression of stemness genes, including BMI1, Oct4, and Sox2. In conclusion, the NQO1 expression in triple-negative breast cancer cells determined their radiosensitivity and was controlled by NEAT1. In addition, NOQ1 bioactivatable compounds displayed potential for application in the development of radiation sensitizers in breast cancer.

Withanolide C Inhibits Proliferation of Breast Cancer Cells via Oxidative Stress-Mediated Apoptosis and DNA Damage.

Some withanolides, particularly the family of steroidal lactones, show anticancer effects, but this is rarely reported for withanolide C (WHC)-especially anti-breast cancer effects. The subject of this study is to evaluate the ability of WHC to regulate the proliferation of breast cancer cells, using both time and concentration in treatment with WHC. In terms of ATP depletion, WHC induced more antiproliferation to three breast cancer cell lines, SKBR3, MCF7, and MDA-MB-231, than to normal breast M10 cell lines. SKBR3 and MCF7 cells showing higher sensitivity to WHC were used to explore the antiproliferation mechanism. Flow cytometric apoptosis analyses showed that subG1 phase and annexin V population were increased in breast cancer cells after WHC treatment. Western blotting showed that cleaved forms of the apoptotic proteins poly (ADP-ribose) polymerase (c-PARP) and cleaved caspase 3 (c-Cas 3) were increased in breast cancer cells. Flow cytometric oxidative stress analyses showed that WHC triggered reactive oxygen species (ROS) and mitochondrial superoxide (MitoSOX) production as well as glutathione depletion. In contrast, normal breast M10 cells showed lower levels of ROS and annexin V expression than breast cancer cells. Flow cytometric DNA damage analyses showed that WHC triggered γH2AX and 8-oxo-2'-deoxyguanosine (8-oxodG) expression in breast cancer cells. Moreover, N-acetylcysteine (NAC) pretreatment reverted oxidative stress-mediated ATP depletion, apoptosis, and DNA damage. Therefore, WHC kills breast cancer cells depending on oxidative stress-associated mechanisms.

Combined Treatment with Low Cytotoxic Ethyl Acetate Nepenthes Extract and Ultraviolet-C Improves Antiproliferation to Oral Cancer Cells via Oxidative Stress.

Ultraviolet-C (UVC) irradiation provides an alternative radiotherapy to X-ray. UVC sensitizer from natural products may improve radiotherapy at low cytotoxic side effects. The aim of this study is to assess the regulation for oral cancer cell proliferation by a combined treatment of UVC and our previously reported anti-oral cancer natural product (ethyl acetate extract of Nepenthes adrianii × clipeata; EANA). The detailed possible UVC sensitizing mechanisms of EANA such as effects on cell proliferation, cell cycle, apoptosis, and DNA damage are investigated individually and in combination using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) assay, flow cytometry, and western blotting at low dose conditions. In a 24 h MTS assay, the low dose EANA (5 µg/mL) and low dose UVC (12 J/m2) individually show 80% and combinedly 57% cell proliferation in oral cancer Ca9-22 cells; but no cytotoxicity to normal oral HGF-1 cells. Mechanistically, low dose EANA and low dose UVC individually induce apoptosis (subG1 accumulation, pancaspase activation, and caspases 3, 8, 9), oxidative stress (reactive oxygen species, mitochondrial superoxide, and mitochondrial membrane potential depletion), and DNA damage (γH2AX and 8-hydroxy-2'-deoxyguanosine). Moreover, the combined treatment (UVC/EANA) synergistically induces these changes. Combined low dose treatment-induced antiproliferation, apoptosis, oxidative stress, and DNA damage were suppressed by the ROS scavenger N-acetylcysteine. In conclusion, UVC/EANA shows synergistic antiproliferation, oxidative stress, apoptosis, and DNA damage to oral cancer cells in an oxidative stress-dependent manner. With the selective killing properties of low dose EANA and low dose UVC, EANA provides a novel UVC sensitizing agent to improve the anti-oral cancer therapy.

Combined Treatment of Sulfonyl Chromen-4-Ones (CHW09) and Ultraviolet-C (UVC) Enhances Proliferation Inhibition, Apoptosis, Oxidative Stress, and DNA Damage against Oral Cancer Cells.

The sensitizing effect of chromone-derived compounds on UVC-induced proliferation inhibition has not been comprehensively investigated so far. The subject of this study was to examine the proliferation change of oral cancer cells while using the combined treatment of UVC (254 nm) with our previously developed sulfonyl chromen-4-ones (CHW09), namely UVC/CHW09. Cell viability, apoptosis, oxidative stress, and DNA damage for the individual and combined treatments for UVC and/or CHW09 were examined in oral cancer Ca9-22 cells. In 24 h MTS assay, UVC (30 J/m2; UVC30), or CHW09 (25 and 50 µg/mL; namely, CHW09-25 and CHW09-50) show 54%, 59%, and 45% viability. The combined treatment (UVC30/CHW09-25 and UVC30/CHW09-50) show lower cell viability (45% and 35%). Mechanistically, UVC/CHW09 induced higher apoptosis than individual treatments and untreated control, which were supported by the evidence of flow cytometry for subG1, annexin V/7-aminoactinomycin D, pancaspase and caspases 3/7 activity, and western blotting for cleaved poly(ADP-ribose) polymerase. Moreover, this cleaved PARP expression was downregulated by pancaspase inhibitor Z-VAD-FMK. UVC/CHW09 showed higher oxidative stress than individual treatments and untreated control in terms of flow cytometry for reactive oxygen species, mitochondrial membrane potential, and mitochondrial mass. Furthermore, UVC/CHW09 showed higher DNA damage than individual treatments and untreated control in terms of flow cytometry for H2A histone family member X and 8-oxo-2'-deoxyguanosine. In conclusion, combined treatment UVC/CHW09 suppresses proliferation, and promotes apoptosis, oxidative stress, and DNA damage against oral cancer cells, providing a novel application of sulfonyl chromen-4-ones in order to sensitize UVC induced proliferation inhibition for oral cancer therapy.

Challenges of BCLC stage C hepatocellular carcinoma: Results of a single-institutional experience on stereotactic body radiation therapy.

In this study, we evaluated the feasibility and efficacy of stereotactic body radiation therapy (SBRT) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC).This retrospective study evaluated 139 patients with BCLC stage C HCC who underwent CyberKnife SBRT between January 2009 and September 2017. All patients had BCLC-C, Child-Turcotte-Pugh score A-B. In-field control, overall survival (OS), progression free survival (PFS), and prognostic factors were evaluated.An objective response rate was achieved in 81.5% patients (complete response, 36.2%, partial response, 45.3%). The median survival was 15.44 months, and the 1-, 3-, 5-year OS rates were 56%, 28%, and 20%, respectively. The median PFS was 6 months, the PFS rate at 1-, 3-, and 5-year were 35%, 14%, and 10%, respectively. In-field control of 1 to 2 years was achieved in 85.1% of patients. The major pattern of failure was out-field intrahepatic failure which comprised 42.9% of patients. Multivariate analysis revealed that the Child-Turcotte-Pugh score, macrovascular invasion, advance stage (III-IV), and tumor response rate were independent predictors of OS.The result of our study shows that SBRT is a safe and effective therapeutic option for BCLC stage C HCC lesions that are unsuitable for standard loco-regional therapies, Moreover, SBRT has acceptable local control rates and low-treatment toxicity.

Antimycin A shows selective antiproliferation to oral cancer cells by oxidative stress-mediated apoptosis and DNA damage.

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration- and exposure time-effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9-22 cell lines than normal oral HGF-1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan-caspase activation in oral cancer CAL 27 and Ca9-22 cells than in normal oral HGF-1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA-induced oxidative stress changes in oral cancer CAL 27 and Ca9-22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9-22 cells and cleaved forms of poly (ADP-ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis-inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine [8-oxodG]) in CAL 27 and Ca9-22 cells. Notably, the AMA-induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N-acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress-dependent mechanism involving apoptosis and DNA damage.

Whole Pelvic Radiotherapy With Stereotactic Body Radiotherapy Boost vs. Conventionally Fractionated Radiotherapy for Patients With High or Very High-Risk Prostate Cancer.

Background: Whole pelvic radiotherapy (WPRT) with stereotactic body radiotherapy (SBRT) boost has been shown to be effective in patients with high-risk prostate cancer (PC). However, no study has directly compared the efficacy of WPRT with SBRT boost with that of conventionally fractionated radiotherapy (CFRT). We compared the clinical outcomes between CFRT and WPRT with SBRT boost in patients with high or very high-risk PC (National Comprehensive Cancer Network definition). Methods: In total, 132 patients treated with CFRT and 121 patients treated with WPRT followed by SBRT boost were retrospectively analyzed. For the CFRT group, the prescribed dose range was 74-79.2 Gray (Gy) administered at 1.8-2 Gy per fraction. For WPRT with SBRT boost, the prescribed doses were 45 Gy administered in 25 fractions to the whole pelvis followed by 21 Gy boost (3 fractions of 7 Gy each) to prostate and seminal vesicles. The overall survival (OS) and biochemical failure (Phoenix definition) free survival (bFFS) were assessed by using the Kaplan-Meier method or the Cox proportional hazards regression model. The gastrointestinal (GI) and genitourinary (GU) tract toxicity were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results: The estimated 4-years overall survival in the CFRT and WPRT with SBRT boost groups was 91.6 and 97.7%, respectively (P = 0.18). The estimated 4-years biochemical failure-free survival in the CFRT and WPRT with SBRT boost groups was 89.1 and 93.9%, respectively (P = 0.41). No acute grade 3 or higher GI and GU toxicity was observed in both groups. Late grade 3 GI and GU toxicity occurred in 2.3 and 2.3% in the CFRT group, and in 1.7 and 0.8% in the WPRT with SBRT boost group, respectively. There was no significant between-group difference with respect to acute or late toxicity. Conclusions: In patients with high or very high-risk localized PC, compared with CFRT, WPRT with SBRT boost resulted in similar biochemical-free and overall survival rate with minimal toxicity. WPRT with SBRT boost is a feasible option for patients with high or very high-risk PC.