Interface chemistry of two-dimensional heterostructures - fundamentals to applications.

Two-dimensional heterostructures (2D HSs) have emerged as a new class of materials where dissimilar 2D materials are combined to synergise their advantages and alleviate shortcomings. Such a combination of dissimilar components into 2D HSs offers fascinating properties and intriguing functionalities attributed to the newly formed heterointerface of constituent components. Understanding the nature of the surface and the complex heterointerface of HSs at the atomic level is crucial for realising the desired properties, designing innovative 2D HSs, and ultimately unlocking their full potential for practical applications. Therefore, this review provides the recent progress in the field of 2D HSs with a focus on the discussion of the fundamentals and the chemistry of heterointerfaces based on van der Waals (vdW) and covalent interactions. It also explains the challenges associated with the scalable synthesis and introduces possible methodologies to produce large quantities with good control over the heterointerface. Subsequently, it highlights the specialised characterisation techniques to reveal the heterointerface formation, chemistry and nature. Afterwards, we give an overview of the role of 2D HSs in various emerging applications, particularly in high-power batteries, bifunctional catalysts, electronics, and sensors. In the end, we present conclusions with the possible solutions to the associated challenges with the heterointerfaces and potential opportunities that can be adopted for innovative applications.

The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients.

PURPOSE: Long-term androgen deprivation therapy has been associated with decreased bone mineral density in men with prostate cancer. Some evidence suggests that there is no impact on fracture risk despite this bone mineral density loss. Our study aimed to quantify changes in bone mineral density in men with high risk prostate cancer on long-term androgen deprivation therapy and calcium and vitamin D supplementation. MATERIALS AND METHODS: Bone mineral density analysis was conducted for localized high risk prostate cancer patients enrolled in the phase III randomized trial PCS-V (Prostate Cancer Study 5), comparing conventional and hypofractionated radiation therapy. Patients received 28 months of luteinizing hormone-releasing hormone agonist and calcium and vitamin D supplementation (500 mg calcium BID+400 IU vitamin D3 BID). The areal density and T-scores (spine, femoral neck and total femur) at baseline and 30 months of followup were extracted, and the absolute change was calculated. Clinical bone density status (normal, osteopenia, osteoporosis) was monitored. RESULTS: The lumbar spine, femoral neck and total femoral bone mineral density were measured for 226, 231, and 173 patients, respectively. The mean percent change in bone mineral density was -2.65%, -2.76% and -4.27% for these respective sites (p <0.001 for all). The average decrease in bone mineral density across all sites was -3.2%, with no decline in bone mineral density category in most patients (83%). Eight patients (4%) became osteoporotic. CONCLUSIONS: Despite a mild decline in bone mineral density, the change in clinical bone mineral density category remained low with long-term androgen deprivation therapy. Consequently, calcium and vitamin D supplementation alone may suffice for most localized prostate cancer patients on long-term androgen deprivation therapy.

Wafer-Sized Ultrathin Gallium and Indium Nitride Nanosheets through the Ammonolysis of Liquid Metal Derived Oxides.

We report the synthesis of centimeter sized ultrathin GaN and InN. The synthesis relies on the ammonolysis of liquid metal derived two-dimensional (2D) oxide sheets that were squeeze-transferred onto desired substrates. Wurtzite GaN nanosheets featured typical thicknesses of 1.3 nm, an optical bandgap of 3.5 eV and a carrier mobility of 21.5 cm2 V-1 s-1, while the InN featured a thickness of 2.0 nm. The deposited nanosheets were highly crystalline, grew along the (001) direction and featured a thickness of only three unit cells. The method provides a scalable approach for the integration of 2D morphologies of industrially important semiconductors into emerging electronics and optical devices.

Different antiviral activities of natural APOBEC3C, APOBEC3G, and APOBEC3H variants against hepatitis B virus.

Some APOBEC3 family members have antiviral activity against retroviruses and DNA viruses. Hepatitis B virus (HBV) is a DNA virus that is the major causative factor of severe liver diseases such as cirrhosis and hepatocellular carcinoma. To determine whether APOBEC3 variants in humans have different anti-HBV activities, we evaluated natural variants of APOBEC3C, APOBEC3G, and APOBEC3H using an HBV-replicating cell culture model. Our data demonstrate that the APOBEC3C variant S188I had increased restriction activity and hypermutation frequency against HBV DNA. In contrast, the APOBEC3G variant H186R did not alter the anti-HBV and hypermutation activities. Among APOBEC3H polymorphisms (hap I-VII) and splicing variants (SV-200, SV-183, SV-182, and SV-154), hap II SV-183 showed the strongest restriction activity. These data suggest that the genetic variations in APOBEC3 genes may affect the efficiency of HBV elimination in humans.

Efficient purification and reconstitution of ATP binding cassette transporter B6 (ABCB6) for functional and structural studies.

The mitochondrial ATP binding cassette transporter ABCB6 has been associated with a broad range of physiological functions, including growth and development, therapy-related drug resistance, and the new blood group system Langereis. ABCB6 has been proposed to regulate heme synthesis by shuttling coproporphyrinogen III from the cytoplasm into the mitochondria. However, direct functional information of the transport complex is not known. To understand the role of ABCB6 in mitochondrial transport, we developed an in vitro system with pure and active protein. ABCB6 overexpressed in HEK293 cells was solubilized from mitochondrial membranes and purified to homogeneity. Purified ABCB6 showed a high binding affinity for MgATP (Kd = 0.18 µM) and an ATPase activity with a Km of 0.99 mM. Reconstitution of ABCB6 into liposomes allowed biochemical characterization of the ATPase including (i) substrate-stimulated ATPase activity, (ii) transport kinetics of its proposed endogenous substrate coproporphyrinogen III, and (iii) transport kinetics of substrates identified using a high throughput screening assay. Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport. These results suggest a direct interaction between mitochondrial ABCB6 and its transport substrates that is critical for the activity of the transporter. Furthermore, the simple immunoaffinity purification of ABCB6 to near homogeneity and efficient reconstitution of ABCB6 into liposomes might provide the basis for future studies on the structure/function of ABCB6.

Surface topography, structural, optical and dc electrical behaviors of pristine and Co-doped ZnS thin films.

The prime goal of the present research is to synthesize pristine zinc sulfide (PZS) and cobalt (Co)-doped zinc sulfide (CDZS) thin films with different doping concentrations (DC) via chemical bath deposition (CBD) method. The effect of Co-doping on the surface topography, structural, optical and dc-electrical behaviors of PZS thin films has been ascertained. Scanning electron microscopy images exhibited nearly sphere-shaped agglomerates of grains dispersed throughout the surface with cracks in PZS thin film whereas cracks were absent in CDZS. Atomic force microscopy image displayed smooth surface of CDZS thin film with evenly dispersed small grains. The hexagonal wurtzite structure of PZS and CDZS thin films with varied X-ray diffraction (XRD) parameters was confirmed via XRD analysis. Optical investigation revealed that the optical direct band gap energy increased with decreasing DC from 12 % to 4 %. Alteration of other optical parameters namely absorption coefficient, extinction coefficient, refractive index, real and imaginary parts of dielectric constant, etc. with DC was also discussed. Direct current electrical investigation revealed that the current-voltage characteristics are linear for all thin films signifying that the electrical conduction in CDZS is ohmic in nature.

Hypofractionated Dose Escalation Radiotherapy for High-risk Prostate Cancer: The Survival Analysis of the Prostate Cancer Study 5, a Groupe de Radio-oncologie Génito-urinaire du Quebec-led Phase 3 Trial.

BACKGROUND AND OBJECTIVE: Prostate Cancer Study 5 (PCS5) compared conventional fractionated radiotherapy (CFRT) with hypofractionated radiotherapy (HFRT) in high-risk prostate cancer (PCa) patients, hypothesizing similar toxicity and survival outcomes. This report presents the efficacy analysis. METHODS: PCS5 is a Canadian multicenter, open-label, phase 3 randomized control trial. Men with histologically proven, clinically localized PCa with one or more high-risk features (T3/T4, Gleason score ≥8, and prostate-specific antigen >20) were eligible. Patients were randomized 1:1 to CFRT (76 Gy/38 fractions [Fx] to the prostate and 46 Gy/23 Fx to the pelvic lymph nodes [PLNs]) or HFRT (68 Gy/25 Fx to the prostate and 45 Gy/25 Fx to the PLNs) and 28 mo of androgen suppression. The primary endpoint was toxicity; secondary endpoints included survival outcomes. KEY FINDINGS AND LIMITATIONS: Of 329 patients, 164 were randomized to HFRT and 165 to CFRT, with 159 in the HFRT arm and 160 in the CFRT arm included in survival analyses. At the 5-yr median follow-up, there were no significant differences in overall survival (OS; 90.3% vs 89.7%; risk ratio [RR]: 1.01; 95% confidence interval [CI]: 0.93-1.09), PCa-specific survival (PCSS; 97.4% vs 97.5%; RR: 1.00; 95% CI: 0.93-1.07), biochemical recurrence-free survival (BCRFS; 85.2% vs 85.2%; RR: 1.00; 95% CI: 0.91-1.10), or distant metastasis-free survival (DMFS; 87.1% vs 87.1%; RR: 1.00; 95% CI: 0.92-1.09). Hazard ratios were 0.92 (95% CI: 0.56-1.53) for OS, 1.31 (95% CI: 0.46-3.78) for PCSS, 0.85 (95% CI: 0.56-1.30) for BCRFS, and 0.90 (95% CI: 0.56-1.43) for DMFS. Sample size was a limiting factor. CONCLUSIONS AND CLINICAL IMPLICATIONS: There were no differences in survival outcomes between HFRT (68 Gy/25 Fx) and CFRT (76 Gy/38 Fx). HFRT, including PLN radiotherapy and long-term androgen deprivation therapy, should be considered a new standard of care for high-risk PCa patients undergoing external beam radiotherapy.

The Outcome of Scaphoid Fracture Nonunion Managed by 1,2 Intercompartmental Supraretinacular Artery (1,2 ICSRA) Vascularized Bone Graft.

BACKGROUND: Scaphoid fracture is most often missed and mismanaged leading to scaphoid nonunion with or without avascular necrosis. When avascular necrosis of the proximal pole is confirmed with intraoperative evaluation, conventional bone graft is not enough. The treatment modalities are evolving day by day. The current trend is vascular bone grafting, which has shown good outcomes in terms of union and wrist function. METHODS: Fifty patients with nonunion fracture of the scaphoid were treated with vascularized pedicle bone graft from the dorsum of the distal radius using the 1st and 2nd intercompartmental supraretinacular artery, from 2014 to 2022. Preoperative and postoperative clinical evaluation included pain, range of motion, grip strength, and satisfaction. The average follow-up period was 12 months. RESULTS: Among 18 patients, 14 were clinically improved after a mean follow-up period of eight weeks. Thirteen patients reported the absence of any discomfort, three patients reported slight discomfort after hard work, and two patients reported pain with light work. The wrist range of motion improved significantly, and the hand grip strength also improved. According to the modified Mayo wrist scoring chart, clinical results were rated as excellent in 24 cases, good in 19 cases, and poor in four cases. CONCLUSION: 1,2 intercompartmental supraretinacular artery (1,2 ICSRA) is superficial to the extensor retinaculum and is a proper pedicle of vascularized bone graft due to the ease of visibility and dissection. The functional results and union rates were satisfactory in our study.

Investigating the aggressiveness of the COVID-19 Omicron variant and suggestions for possible treatment options.

The COVID-19 pandemic has put a strain on all the healthcare systems around the world. The World Health Organization (WHO) stated that the "highly mutated" Omicron variant, known as B.1.1.529, could represent a very high global risk of sudden increases in infections. As a result, it is urgently necessary to explore the most suitable treatments for this variant. The purpose of the study was to investigate the currently available studies regarding the Omicron variant and try to identify any potentially effective therapies for the Omicron variant.

Rohingya refugees in the pandemic: Crisis and policy responses.

The purpose of this article is to demonstrate how a lack of policy attention has exacerbated the extreme circumstances faced by the Rohingya and how they can contribute to deterioration of their health, livelihood, and education, as well as their repatriation to their homeland. This article is based on data collected from field observations and interviews prior to and during the pandemic. This study confirms that the Rohingya refugee populations endure a higher level of suffering from lack of food security and livelihood, lack of basic amenities and financial resources, and accommodation is overcrowded compared with the pre-pandemic period. The lack of a specific policy for the Rohingya has compounded the current situation in Bangladesh. This research is crucial for countries receiving refugees as well as the countries from which they flee and other actors.

Fecal microbiota transplantation for Carbapenem-Resistant Enterobacteriaceae: A systematic review.

The prevalence of Carbapenem-resistant Enterobacteriaceae (CRE) has increased dramatically in recent years and has become a global public health issue. Since carbapenems are considered the last drugs of choice, infections caused by these pathogens are difficult to treat and carry a high risk of mortality. Several antibiotic combination regimens have been utilized for the management of CRE infections or to eradicate colonization in CRE carriers with variable clinical responses. In addition, recent studies have explored the use of fecal microbiota transplantation (FMT) to eradicate CRE infections. Here, we conducted a systematic review of publications in which FMT was used to eliminate CRE colonization in infected individuals. We searched the PubMed, Cochrane, and Medline databases up to November 30, 2021. Ten studies (209 patients) met the inclusion criteria for this review with three articles describing retrospective cohorts (n = 53 patients) and seven reporting prospective data (n = 156 patients), including one randomized open-label clinical trial. All studies were published between 2017 and 2021 with eight studies from Europe and two from South Korea. There were substantial variations in terms of outcome measurements and study endpoint among these studies. Among the 112 FMT recipients with confirmed CRE colonization, CRE decolonization was reported in 55/90 cases at one month after FMT and at the end of the study follow-up (6-12 months), decolonization was documented in 74/94 (78.7%) patients. The predominant CRE strains reported were Klebsiella pneumoniae and Escherichia coli and the most frequently documented carbapenemases were KPC, OXA-48, and NDM. In general, FMT was well tolerated, with no severe complications reported even in immunosuppressed patients and in those with multiple underlying conditions. In conclusion, FMT appears to be safe and effective in eradicating CRE colonization, however, more studies, especially randomized trials, are needed to validate the safety and clinical utility of FMT for CRE eradication.

Hetero-metallic metal-organic frameworks for room-temperature NO2 sensing.

Metal-organic frameworks (MOFs) with exceptional features such as high structural diversity and surface area as well as controlled pore size has been considered a promising candidate for developing room temperature highly-sensitive gas sensors. In comparison, the hetero-metallic MOFs with redox-active open-metal sites and mixed metal nodes may create peculiar surface properties and synergetic effects for enhanced gas sensing performances. In this work, the Fe atoms in the Fe3 (Porous coordination network) PCN-250 MOFs are partially replaced by transition metal Co, Mn, and Zn through a facile hydrothermal approach, leading to the formation of hetero-metallic MOFs (Fe2IIIMII, M = Co, Mn, and Zn). While the PCN-250 framework is maintained, the morphological and electronic band structural properties are manipulated upon the partial metal replacement of Fe. More importantly, the room temperature NO2 sensing performances are significantly varied, in which Fe2Mn PCN-250 demonstrates the largest response magnitude for ppb-level NO2 gas compared to those of pure Fe3 PCN-250 and other hetero-metallic MOF structures mainly attributed to the highest binding energy of NO2 gas. This work demonstrates the strong potential of hetero-metallic MOFs with carefully engineered substituted metal clusters for power-saving and high-performance gas sensing applications.

The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-ß.

Although a glycosylphosphatidylinositol-anchored protein (GPI-AP) CD109 serves as a TGF-ß co-receptor and inhibits TGF-ß signaling in keratinocytes, the role of CD109 on hematopoietic stem progenitor cells (HSPCs) remains unknown. We studied the effect of CD109 knockout (KO) or knockdown (KD) on TF-1, a myeloid leukemia cell line that expresses CD109, and primary human HSPCs. CD109-KO or KD TF-1 cells underwent erythroid differentiation in the presence of TGF-ß. CD109 was more abundantly expressed in hematopoietic stem cells (HSCs) than in multipotent progenitors and HSPCs of human bone marrow (BM) and cord blood but was not detected in mouse HSCs. Erythroid differentiation was induced by TGF-ß to a greater extent in CD109-KD cord blood or iPS cell-derived megakaryocyte-erythrocyte progenitor cells (MEPs) than in wild-type MEPs. When we analyzed the phenotype of peripheral blood MEPs of patients with paroxysmal nocturnal hemoglobinuria who had both GPI(+) and GPI(-) CD34+ cells, the CD36 expression was more evident in CD109- MEPs than CD109+ MEPs. In summary, CD109 suppresses TGF-ß signaling in HSPCs, and the lack of CD109 may increase the sensitivity of PIGA-mutated HSPCs to TGF-ß, thus leading to the preferential commitment of erythroid progenitor cells to mature red blood cells in immune-mediated BM failure.

Experimental and theoretical examination of surface energy and adhesion of nitrifying and heterotrophic bacteria using self-assembled monolayers.

Biofilm-based systems, including integrated fixed-film activated sludge and moving bed bioreactors, are becoming increasingly popular for wastewater treatment, often with the goal of improving nitrification through the enrichment of ammonia and nitrite oxidizing bacteria. We have previously demonstrated the utility of self-assembled monolayers (SAMs) as tools for studying the initial attachment of bacteria to substrata systematically varying in physicochemical properties. In this work, we expanded these studies to bacteria of importance in wastewater treatment systems and we demonstrated attachment rates were better correlated with surface energy than with wettability (water contact angle). Toward the long-term goal of improving wastewater treatment performance through the strategic design of attachment substrata, the attachment rates of two autotrophic ammonia-oxidizing bacteria (Nitrosomonas europaea and Nitrosospira multiformis) and a heterotroph (Escherichia coli) were evaluated using SAMs with a range of wettabilities, surface energies, and functional properties (methyl, hydroxyl, carboxyl, trimethylamine, and amine terminated). Cell attachment rates were somewhat correlated with the water contact angles of the SAMs with polar terminal groups (hydroxyl, carboxyl, trimethylamine, and amine). Including all SAM surfaces, a better correlation was found for all bacteria between attachment rates and surface free energy, as determined using the Lewis Acid-Base approach. The ammonia-oxidizers had higher adhesion rates on the SAMs with higher surface energies than did the heterotroph. This work demonstrated the successful application of SAMs to determine the attachment surface preferences of bacteria important to wastewater treatment, and it provides guidance for a new area of research aimed at improving treatment performance through rational attachment surface design.

Characterization and effect of biofouling on polyamide reverse osmosis and nanofiltration membrane surfaces.

Biofouling is a major reason for flux decline in the performance of membrane-based water and wastewater treatment plants. Initial biochemical characterization of biofilm formation potential and biofouling on two commercially available membrane surfaces from FilmTec Corporation were investigated without filtration in laboratory rotating disc reactor systems. These surfaces were polyamide aromatic thin-film reverse osmosis (RO) (BW30) and semi-aromatic nanofiltration (NF270) membranes. Membrane swatches were fixed on removable coupons and exposed to water with indigenous microorganisms supplemented with 1.5 mg l(-1) organic carbon under continuous flow. After biofilms formed, the membrane swatches were removed for analyses. Staining and epifluorescence microscopy revealed more cells on the RO than on the NF surface. Based on image analyses of 5-µm thick cryo-sections, the accumulation of hydrated biofoulants on the RO and NF surfaces exceeded 0.74 and 0.64 µm day(-1), respectively. As determined by contact angle the biofoulants increased the hydrophobicity up to 30° for RO and 4° for NF surfaces. The initial difference between virgin RO and NO hydrophobicities was ∼5°, which increased up to 25° after biofoulant formation. The initial roughness of RO and NF virgin surfaces (75.3 nm and 8.2 nm, respectively) increased to 48 nm and 39 nm after fouling. A wide range of changes of the chemical element mass percentages on membrane surfaces was observed with X-ray photoelectron spectroscopy. The initial chemical signature on the NF surface was better restored after cleaning than the RO membrane. All the data suggest that the semi-aromatic NF surface was more biofilm resistant than the aromatic RO surface. The morphology of the biofilm and the location of active and dead cell zones could be related to the membrane surface properties and general biofouling accumulation was associated with changes in the surface chemistry of the membranes, suggesting the validity of the combination of these novel approaches for initial assessment of membrane performance.

Cisplatin Activates the Growth Inhibitory Signaling Pathways by Enhancing the Production of Reactive Oxygen Species in Non-small Cell Lung Cancer Carrying an EGFR Exon 19 Deletion.

BACKGROUND/AIM: Cisplatin is a potent anticancer drug for treating several types of cancer, including non-small-cell lung cancer (NSCLC). In this study, we investigated the cytotoxicity and mechanism of action of cisplatin in the human NSCLC cell line PC9. MATERIALS AND METHODS: PC9 cells were treated with cisplatin for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, membrane permeability assay, cell cycle assay, ROS assay, SA-ß-gal staining, TUNEL assay and Western blotting. RESULTS: Our findings revealed that the cytotoxic activity was associated with an apoptotic signaling pathway in response to DNA damage. Cisplatin exerted a significant concentration-dependent antiproliferative effect on PC9 cells. Cells subjected to cisplatin treatment showed morphological indications of apoptosis. Cell cycle arrest was related to the restriction of E2F-1 action by the cyclin-dependent protein kinase inhibitor p21WAF1/CIP1 Cisplatin induced apoptosis of PC9 cells by upregulating Fas, FasL, Bak, and tBID expression and PARP proteolytic cleavage. Cisplatin also reduced the mitochondrial membrane potential (MMP) and initiated a caspase cascade. Furthermore, the apoptotic impact of cisplatin depended on reactive oxygen species (ROS), as confirmed by ROS generation. CONCLUSION: Cisplatin induced anticancer effects through cell cycle arrest, ROS generation and caspase activation, resulting in cell apoptosis. Overall, the results show the mechanism by which cisplatin works as an anticancer drug in the treatment of NSCLC.

Pemetrexed Disodium Heptahydrate Induces Apoptosis and Cell-cycle Arrest in Non-small-cell Lung Cancer Carrying an EGFR Exon 19 Deletion.

BACKGROUND/AIM: Non-small-cell lung cancer (NSCLC) remains a significant cause of death despite the recent introduction of several improved therapeutics. Pemetrexed disodium heptahydrate (pemetrexed) is currently available in combination with a platinum derivative for patients with advanced non-squamous NSCLC for first-line treatment, and as a single agent for second-line treatment. However, the mechanisms underlying its anticancer activities are still not well understood. In this study, we evaluated the growth inhibitory effects of pemetrexed on PC9 (EGFR exon 19 deletion) cells and elucidated the underlying molecular mechanisms. MATERIALS AND METHODS: PC9 cells were treated with pemetrexed and then assessed for the cell viability, morphological and nuclear changes, antigenic alterations, SA-ß-gal staining, and changes in protein expression. RESULTS: Pemetrexed reduced the cell viability of PC9 cells and initiated cell morphological changes in a concentration-dependent manner. Pemetrexed significantly induced G1 phase arrest in a dose-dependent manner. The results demonstrated that pemetrexed induced apoptosis in PC9 cells, a change coupled with an increase in reactive oxygen species and a decrease in mitochondrial membrane potential. Pemetrexed decreased Bcl-2 expression, while Bax expression was increased, and cytochrome c was released. Furthermore, the expression of extrinsic pathway proteins, e.g. Fas/FasL, DR4/TRAIL, and Fas-associated protein with death domain, was increased by pemetrexed, which then activated caspase-8, caspase-9, and caspase-3 and induced poly (ADP-ribose) polymerase proteolysis. CONCLUSION: This study revealed the mechanisms by which pemetrexed works an anticancer drug in the treatment of NSCLC.

The emerging role of cellular senescence in complications of COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has triggered a sudden global change in healthcare systems. Cancer patients have a higher risk of death from COVID-19 in comparison to patients without cancer. Many studies have stated that various factors, such as older age, frequent exposure to healthcare, and higher smoking rates are responsible for the complications of COVID-19. We hypothesize that side effects of chemotherapy, such as cellular senescence, could worsen COVID-19. Given this situation, in this review, we highlight the updated findings of research investigating the impact of cellular senescence on COVID-19 complications and explored potential therapeutic targets for eliminating senescent cells during the COVID-19 pandemic.

Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in Monotherapy and Combination Therapy on KRAS-dependent A549 Lung Cancer Cells.

BACKGROUND/AIM: Cisplatin combined with pemetrexed disodium heptahydrate (pemetrexed) is considered the standard treatment for patients with advanced, non-squamous, non-small-cell lung cancer. However, its growth-inhibitory effects on KRAS-dependent lung cancer as monotherapy and combination therapy are not well understood. The aim of this study was to compare the effects of cisplatin and pemetrexed on A549 cells as mono- and combination therapies and elucidate the underlying mechanisms. MATERIALS AND METHODS: For in vitro studies, A549 cells were exposed to cisplatin with/without pemetrexed for 72 h. The results were then evaluated by cell viability, apoptosis, reactive oxygen species, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting assays. RESULTS: Our results revealed that cisplatin monotherapy was most cytotoxic to A549 cells, while cisplatin plus pemetrexed combination had an intermediate effect, and pemetrexed monotherapy induced a minimal cytotoxic effect on A549 cells. This effect was evidenced by cell viability results, inhibition of KRAS proto-oncogene, GTPase (KRAS)/Raf proto-oncogene, serine/threonine kinase/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and apoptosis induction triggered by reactive oxygen species-mediated DNA damage. The immunoblotting result of conversion of microtubule-associated protein 1 light chain 3 alpha (LC3)-I to -II indicated that the greatest inducer of autophagy was combined treatment with cisplatin plus pemetrexed, while pemetrexed monotherapy had the lowest effect on autophagy induction, with cisplatin monotherapy having an intermediate effect. We found that the AKT serine/threonine kinase 1/mechanistic target of rapamycin kinase (mTOR) and AMP-activated protein kinase/mTOR signaling pathways were associated with autophagy activation. Interestingly, combination therapy with cisplatin plus pemetrexed was the primary eliminator of cellular senescence; cisplatin monotherapy had an intermediate effect, while pemetrexed monotherapy increased cellular senescence of A549 cells, as assessed by the expression of ß-galactosidase protein. CONCLUSION: Cisplatin monotherapy may be more effective than pemetrexed monotherapy or cisplatin plus pemetrexed combination therapy against KRAS-dependent lung cancer.

The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells.

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) poses a great challenge for the treatment of cancer patients. It presents as a severe respiratory infection in aged individuals, including some lung cancer patients. COVID-19 may be linked to the progression of aggressive lung cancer. In addition, the side effects of chemotherapy, such as chemotherapy resistance and the acceleration of cellular senescence, can worsen COVID-19. Given this situation, we investigated the role of paclitaxel (a chemotherapy drug) in the cell proliferation, apoptosis, and cellular senescence of gefitinib-resistant non-small-cell lung cancer (NSCLC) cells (PC9-MET) to clarify the underlying mechanisms. MATERIALS AND METHODS: PC9-MET cells were treated with paclitaxel for 72 h and then evaluated by a cell viability assay, DAPI staining, Giemsa staining, apoptosis assay, a reactive oxygen species (ROS) assay, SA-ß-Gal staining, a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay and Western blotting. RESULTS: Paclitaxel significantly reduced the viability of PC9-MET cells and induced morphological signs of apoptosis. The apoptotic effects of paclitaxel were observed by increased levels of cleaved caspase-3 (Asp 175), cleaved caspase-9 (Asp 330) and cleaved PARP (Asp 214). In addition, paclitaxel increased ROS production, leading to DNA damage. Inhibition of ROS production by N-acetylcysteine attenuates paclitaxel-induced DNA damage. Importantly, paclitaxel eliminated cellular senescence, as observed by SA-ß-Gal staining. Cellular senescence elimination was associated with p53/p21 and p16/pRb signaling inactivation. CONCLUSION: Paclitaxel may be a promising anticancer drug and offer a new therapeutic strategy for managing gefitinib-resistant NSCLC during the COVID-19 pandemic.