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Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
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Leucemia-Linfoma de Células T del Adulto , Linfoma , Adulto , Apoptosis/genética , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Humanos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma de Células T del Adulto/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Transducción de SeñalRESUMEN
Dissociative electron transfer in collisions between neutral potassium atoms and neutral ethanol molecules yields mainly OH-, followed by C2H5O-, O-, CH3 - and CH2 -. The dynamics of negative ions have been investigated by recording time-of-flight mass spectra in a wide range of collision energies from 17.5 to 350â eV in the lab frame, where the branching ratios show a relevant energy dependence for low/intermediate collision energies. The dominant fragmentation channel in the whole energy range investigated has been assigned to the hydroxyl anion in contrast to oxygen anion from dissociative electron attachment (DEA) experiments. This result shows the relevant role of the electron donor in the vicinity of the temporary negative ion formed allowing access to reactions which are not thermodynamically attained in DEA experiments. The electronic state spectroscopy of such negative ions, was obtained from potassium cation energy loss spectra in the forward scattering direction at 205â eV impact energy, showing a prevalent Feshbach resonance at 9.36±0.10â eV with σ O H * / σ C H * ${{\sigma }_{OH}^{^{\ast}}/{\sigma }_{CH}^{^{\ast}}}$ character, while a less pronounced σ O H * ${{\sigma }_{OH}^{^{\ast}}}$ contribution assigned to a shape resonance has been obtained at 3.16±0.10â eV. Quantum chemical calculations for the lowest-lying unoccupied molecular orbitals in the presence of a potassium atom have been performed to support the experimental findings.
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In this study, we present a complete set of electron scattering cross-sections from 1-Methyl-5-Nitroimidazole (1M5NI) molecules for impact energies ranging from 0.1 to 1000 eV. This information is relevant to evaluate the potential role of 1M5NI as a molecular radiosensitizers. The total electron scattering cross-sections (TCS) that we previously measured with a magnetically confined electron transmission apparatus were considered as the reference values for the present analysis. Elastic scattering cross-sections were calculated by means of two different schemes: The Schwinger multichannel (SMC) method for the lower energies (below 15 eV) and the independent atom model-based screening-corrected additivity rule with interferences (IAM-SCARI) for higher energies (above 15 eV). The latter was also applied to calculate the total ionization cross-sections, which were complemented with experimental values of the induced cationic fragmentation by electron impact. Double differential ionization cross-sections were measured with a reaction microscope multi-particle coincidence spectrometer. Using a momentum imaging spectrometer, direct measurements of the anion fragment yields and kinetic energies by the dissociative electron attachment are also presented. Cross-sections for the other inelastic channels were derived with a self-consistent procedure by sampling their values at a given energy to ensure that the sum of the cross-sections of all the scattering processes available at that energy coincides with the corresponding TCS. This cross-section data set is ready to be used for modelling electron-induced radiation damage at the molecular level to biologically relevant media containing 1M5NI as a potential radiosensitizer. Nonetheless, a proper evaluation of its radiosensitizing effects would require further radiobiological experiments.
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Electrones , Transporte de Electrón , Fenómenos Físicos , Movimiento (Física)RESUMEN
The objective of this investigation is to provide framework to construct a threefold mixture model and its shifted version using Weibull, lognormal, and gamma distributions. The proposed models are examined by establishing the statistical and reliability indices. The parameter estimation using the maximum likelihood estimation method (MLE) and expectation-maximization has been proposed. The usefulness of the shifted mixture models by fitting them into the actual data set has revealed. The goodness-of-fit tests are used to compare the mixture models for the real-life data. Based on statistical testing, it is established that for small data set, shifted mixture model is the best fitted model in comparison with other single and mixed mixture distributions.
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In this contribution, we report a novel comprehensive investigation on negative ion formation from electron transfer processes mediated by neutral potassium atom collisions with neutral methanol molecules employing experimental and theoretical methodologies. Methanol collision-induced fragmentation yielding anion formation has been obtained by time-of-flight mass spectrometry in the wide energy range of 19 to 275 eV in the lab frame. The negative ions formed in such a collision process have been assigned to CH3O-, OH-, and O-, with a strong energy dependence especially at lower collision energies. The most intense fragment anions in the whole energy range investigated have been assigned to OH- and CH3O-. Additionally, the potassium cation energy loss spectrum in the forward scattering direction at 205 eV impact energy has revealed several features, where the two main electronic states accessible during the collision events have vertical electron affinities of -8.26 ± 0.20 and -10.36 ± 0.2 eV. Quantum chemical calculations have been performed for the lowest-lying unoccupied molecular orbitals of methanol in the presence of a potassium atom, lending strong support to the experimental findings.
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In this study, novel experimental total electron detachment cross sections for O2- collisions with benzene molecules are reported for the impact energy range (10-1000 eV), as measured with a transmission beam apparatus. By analysing the positively charged species produced during the collision events, relative total ionisation cross sections were derived in the incident energy range of 160-900 eV. Relative partial ionisation cross sections for fragments with m/z ≤ 78 u were also given in this energy range. We also confirmed that heavier compounds (m/z > 78 u) formed for impact energies between 550 and 800 eV. In order to further our knowledge about the collision dynamics governing the fragmentation of such heavier molecular compounds, we performed molecular dynamics calculations within the framework of the Density Functional Theory (DFT). These results demonstrated that the fragmentation of these heavier compounds strongly supports the experimental evidence of m/z = 39-42, 50, 60 (u) cations formation, which contributed to the broad local maximum in the total ionisation observed from 550 to 800 eV. This work reveals the reactivity induced by molecular anions colliding with hydrocarbons at high energies, processes that can take place in the interstellar medium under various local conditions.
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Benceno/química , Cationes/química , Superóxidos/química , Aniones/química , Electrones , Espectrometría de Masas , Modelos Químicos , Simulación de Dinámica Molecular , Fenómenos FísicosRESUMEN
The geometrical effect of chlorine atom positions in polyatomic molecules after capturing a low-energy electron is shown to be a prevalent mechanism yielding Cl2-. In this work, we investigated hexachlorobenzene reduction in electron transfer experiments to determine the role of chlorine atom positions around the aromatic ring, and compared our results with those using ortho-, meta- and para-dichlorobenzene molecules. This was achieved by combining gas-phase experiments to determine the reaction threshold by means of mass spectrometry together with quantum chemical calculations. We also observed that Cl2- formation can only occur in 1,2-C6H4Cl2, where the two closest C-Cl bonds are cleaved while the chlorine atoms are brought together within the ring framework due to excess energy dissipation. These results show that a strong coupling between electronic and C-Cl bending motion is responsible for a positional isomeric effect, where molecular recognition is a determining factor in chlorine anion formation.
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This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range of 10-400 eV. The negative ions formed in this energy range were time-of-flight mass analyzed and branching ratios were obtained. Assignment of different anions showed that more than 80% was due to the formation of the non-dissociated parent anion NIMOâ¢- at 226 u and nitrogen dioxide anion NO2- at 46 u. The rich fragmentation pattern revealed that significant collision induced the decomposition of the 4-nitroimidazole ring, as well as other complex internal reactions within the temporary negative ion formed after electron transfer to neutral NIMO. Other fragment anions were only responsible for less than 20% of the total ion yield. Additional information on the electronic state spectroscopy of nimorazole was obtained by recording a K+ energy loss spectrum in the forward scattering direction (θ ≈ 0°), allowing us to determine the most accessible electronic states within the temporary negative ion. Quantum chemical calculations on the electronic structure of NIMO in the presence of a potassium atom were performed to help assign the most significant lowest unoccupied molecular orbitals participating in the collision process. Electron transfer was shown to be a relevant process for nimorazole radiosensitisation through efficient and prevalent non-dissociated parent anion formation.
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Electrones , Nimorazol , Aniones , Transporte de Electrón , Iones , Potasio/químicaRESUMEN
Metastasis is the primary cause of treatment failures and mortality in most cancers. Triple-negative breast cancer (TNBC) is refractory to treatment and rapidly progresses to disseminated disease. We utilized an orthotopic mouse model that molecularly and phenotypically resembles human TNBC to study the effects of exogenous, daily tissue inhibitor of metalloproteinase-2 (TIMP-2) treatment on tumor growth and metastasis. Our results demonstrated that TIMP-2 treatment maximally suppressed primary tumor growth by ~36-50% and pulmonary metastasis by >92%. Immunostaining assays confirmed disruption of the epithelial to mesenchymal transition (EMT) and promotion of vascular integrity in primary tumor tissues. Immunostaining and RNA sequencing analysis of lung tissue lysates from tumor-bearing mice identified significant changes associated with metastatic colony formation. Specifically, TIMP-2 treatment disrupts periostin localization and critical cell-signaling pathways, including canonical Wnt signaling involved in EMT, as well as PI3K signaling, which modulates proliferative and metastatic behavior through p27 phosphorylation/localization. In conclusion, our study provides evidence in support of a role for TIMP-2 in suppression of triple-negative breast cancer growth and metastasis through modulation of the epithelial to mesenchymal transition, vascular normalization, and signaling pathways associated with metastatic outgrowth. Our findings suggest that TIMP-2, a constituent of the extracellular matrix in normal tissues, may have both direct and systemic antitumor and metastasis suppressor effects, suggesting potential utility in the clinical management of breast cancer progression.
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Carcinogénesis/genética , Proliferación Celular/genética , Inhibidor Tisular de Metaloproteinasa-2/genética , Neoplasias de la Mama Triple Negativas/genética , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Humanos , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas , Análisis de Secuencia de ARN , Neoplasias de la Mama Triple Negativas/patología , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We investigate the methanol absorption spectrum in the range 5.5-10.8 eV to provide accurate and absolute cross-sections values. The main goal of this study is to provide a comprehensive analysis of methanol electronic-state spectroscopy by employing high-resolution vacuum ultraviolet (VUV) photoabsorption measurements together with state-of-the-art quantum chemical calculation methods. The VUV spectrum reveals several new features that are not previously reported in literature, for n > 3 in the transitions (nsσ(a') â (2aâ³)) (1A' â XÌ1A') and (nsσ, npσ, npσ', ndσ â (7a')) (1A' â XÌ1A'), and with particular relevance to vibrational progressions of the CH3 rocking mode, v11'(aâ³), mode in the (3pπ(aâ³) â (2aâ³)) (21A' â XÌ1A') absorption band at 8.318 eV. The measured absolute photoabsorption cross-sections have subsequently been used to calculate the photolysis lifetime of methanol in the Earth's atmosphere from the ground level up to the limit of the stratosphere (50 km altitude). This shows that solar photolysis plays a negligible role in the removal of methanol from the lower atmosphere compared with competing sink mechanisms. Torsional potential energy scans, as a function of the internal rotation angle for the ground and first Rydberg states, have also been calculated as part of this investigation.
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Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47-59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2'-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.
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Asma/patología , Hiperreactividad Bronquial/patología , Factor 2 Relacionado con NF-E2/metabolismo , Uniones Estrechas/inmunología , Proteína de la Zonula Occludens-1/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Asma/inducido químicamente , Asma/inmunología , Cadherinas/metabolismo , Chalconas/farmacología , Citocinas/inmunología , Citocinas/metabolismo , Citoprotección , Proteínas del Citoesqueleto/genética , Células Epiteliales/metabolismo , Inflamación/inmunología , Proteína 1 Asociada A ECH Tipo Kelch , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Ovalbúmina , Estrés Oxidativo/inmunología , Mucosa Respiratoria/citología , Células Th2/inmunologíaRESUMEN
Cardiac cysticercosis is a rarely encountered form of cysticercosis, caused by the larval cyst of tapeworm (Taenia solium). It commonly affects the central nervous system; however, systematic involvement has been reported as well. We describe a case of isolated cardiac cysticercosis incidentally discovered in a 16-year-old female undergoing surgical closure of a ventricular septal defect (VSD), with no prior history of parasitic infestation. Our objective is to highlight the importance of cardiac cysticercosis as a differential finding in epicardial cystic masses which may be missed or misinterpreted on imagining modalities and to the limited literature on this particular rate manifestation of cysticercosis.
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PURPOSE: The Hospital Corneal Retrieval Program (HCRP) aims to counsel and encourage the family of a critically ill or deceased person in the hospital for eye donation. Adequately sensitized health-care workers (HCWs) may play a pivotal role in boosting HCRP. STUDY DESIGN: Multicentric, cross-sectional, descriptive study. METHODS: Study participants included all HCWs of three medical colleges, including one with eye bank and corneal transplant services. A pretested, structured questionnaire was used to record the awareness, knowledge, and attitude about eye donation among HCWs. The expected outcome was to seek differences in awareness, if any, among medical and paramedical workers of medical colleges with (group A) or without (group B) eye bank and corneal transplant facilities. RESULTS: Of the 4060 study participants, 2100 HCWs were in group A and the rest (1960) were in group B. For eight out of 13 questions assessing awareness and perception, a statistically insignificant difference in responses was observed between the two groups. Regarding questions related to attitude, although the majority of HCWs in both groups were comfortable talking about eye donation, they did feel that counseling relatives of a terminally ill patient about eye donation was insensitive. Less than half of HCWs showed a willingness to donate eyes, and about half of the participants wanted to acquire more knowledge about eye donation. CONCLUSION: Awareness regarding eye donation among HCWs was mostly found to be at dismal levels, irrespective of whether they worked in an institute with or without eye bank and corneal transplant services. This warrants an accelerated effort at sensitizing HCWs as a strengthening measure for HCRP.
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Trasplante de Córnea , Obtención de Tejidos y Órganos , Humanos , Estudios Transversales , Masculino , Encuestas y Cuestionarios , Femenino , Adulto , Bancos de Ojos , Donantes de Tejidos , Conocimientos, Actitudes y Práctica en Salud , India , Córnea/cirugía , Persona de Mediana EdadRESUMEN
This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: (1) through stepwise changes in the size of the nitrogen-bearing ring; (2) through the oxidation state of the carbon-centered point of diversification; (3) through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic; and (4) through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp(3) carbon content which is essential for the three-dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e., the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to "split the difference" between the two diastereomers by preparation of their corresponding unsaturated version.
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Compuestos Heterocíclicos/síntesis química , Compuestos de Espiro/síntesis química , Compuestos Heterocíclicos/química , Estructura Molecular , Compuestos de Espiro/químicaRESUMEN
Green energy is being claimed as a sustainable solution to the socioeconomic concerns associated with environmental issues and the depletion of non-renewable sources of energy. The impacts of climate change, including global warming, ozone layer depletion, and rising sea levels, have underscored the emergent need for increased investment in green energy to curb down carbon dioxide emissions. Evolution of environmentalism in the 21st century, and the power of environmentally conscious population with their consumption driven demand is increasing which address a wide variety of economic, social, political, technological and legal topics, ranging from empirical analysis to philosophical theorization. This study aims to explore recent advancements in green energy, adaptations to it, and the role of the circular economy within this context. The research employed a review approach, combined with bibliometric analysis of articles published in the past two decades. These articles were obtained from the Scopus database and selected based on specific inclusion and exclusion criteria. To conduct the bibliometric analysis, the authors utilized Bibliometrix R and VOSviewer software, employing analysis like performance analysis, and bibliographic coupling. This study serves as an initiative to identify emerging themes and potential future research areas, with a specific focus on the impact of green energy on industrial and business-to-business sectors and the development of decision-making tools.
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H2O/D2O negative ion time-of-flight mass spectra from electron transfer processes at different collision energies with neutral potassium yield OH-/OD-, O-, and H-/D-. The branching ratios show a relevant energy dependence with an important isotope effect in D2O. Electronic state spectroscopy of water has been further investigated by recording potassium cation energy loss spectra in the forward scattering direction at an impact energy of 205 eV (lab frame), with quantum chemical calculations for the lowest-lying unoccupied molecular orbitals in the presence of a potassium atom supporting most of the experimental findings. The DO-D bond dissociation energy has been determined for the first time to be 5.41 ± 0.10 eV. The collision dynamics revealed the character of the singly excited (1b2-1) molecular orbital and doubly excited states in such K-H2O and K-D2O collisions.
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Primary cardiac synovial sarcoma is a rare entity, arising from the pericardium or the chambers of the heart. It presents in the 4th decade of life with a striking male predisposition. We describe an unusual case of a 22-year-old female who presented with complaints of dyspnoea on exertion, palpitations, and chest pain. Trans-thoracic echocardiography was suggestive of a cystic pericardial mass with pericardial effusion anterior and lateral to the right ventricle. Computed tomography scan (CT scan) revealed thick-walled predominantly cystic lesion over the left ventricle with gross pericardial effusion with internal septations. These findings were suggestive of an infected pericardial cyst. Upon surgery, an adherent mass in the pericardial cavity was found which was not separable from the right heart structures, the great vessels, and the left ventricle. Biopsy was taken, histopathology was suggestive of spindle cell neoplasm, and an immunohistochemistry analysis revealed Transducin-like enhancer of split 1 (TLE 1)-positive malignant spindle cell tumour likely synovial sarcoma. After surgery, the patient received serial adjuvant chemo-radiation therapy. The synovial sarcoma masqueraded as effusive constrictive pericarditis, due to which it eluded preoperative diagnosis.
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Spatial and temporal variations have been found in the levels of arsenic (As) throughout the groundwater of the Ghaghara basin. Fifteen out of twenty-five districts in this basin are reported to be affected by As, where the levels of As in groundwater and soil exceed the permissible limits set by the WHO (10 µgl-1) and FAO (20 mgkg-1) respectively. These districts include a total of four municipalities in Nepal and eighty-six blocks in India, all of which have varying degrees of As contamination. Approximately 17 million people are at risk of As poisoning, with more than two orders of magnitude higher potential lifetime incremental cancer risk, constituting over 153 thousand potential additional cases of cancer due to As-contaminated drinking water. Out of the 90 As-contaminated blocks in the Ghaghara basin, 4 blocks have about 7-fold higher potential risk of developing cancer, 49 blocks have 8-37-fold higher risk, and 37 blocks have up to 375-fold higher risk compared to the upper limit of the USEPA acceptable range, which is 1 × 10-6-1 × 10-4. High accumulation of As has been reported in the nails, hair, and urine of local inhabitants, with higher levels observed in females than males. The toxicity of As is manifested in terms of a higher occurrence of various diseases. Reproductive endpoints, such as increased incidences of preterm birth, spontaneous abortion, stillbirth, low-birth weight, and neonatal death, have also been reported in the basin. The level of As in tube wells has been found to be negatively correlated with the depth (r = -0.906), and tube wells with high levels of As (>150 µgl-1) are generally located within close proximity (<10 km) to abandoned or present meander channels in the floodplain areas of the Ghaghara river. In addition to As contamination, the water quality index (WQI) in the Ghaghara basin is poor according to the BIS standards for drinking water. Groundwater in six out of fifteen districts is unsuitable for drinking purposes, with a WQI exceeding 100. The levels of As in agricultural soil in many villages of Ballia, Bahraich, and Lakhimpur Kheri districts have exceeded the FAO limit. Water from deep tube wells has been found to be relatively safe in terms of As content, and thus can be recommended for drinking purposes. However, the use of surface water needs to be encouraged for irrigation purposes in order to preserve soil health and reduce As contamination in the food chain, thereby minimizing the risk of cancer.
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Arsénico , Agua Potable , Agua Subterránea , Neoplasias , Nacimiento Prematuro , Contaminantes Químicos del Agua , Recién Nacido , Masculino , Embarazo , Femenino , Humanos , Arsénico/análisis , Contaminantes Químicos del Agua/análisis , Neoplasias/epidemiología , Suelo , India/epidemiología , Monitoreo del AmbienteRESUMEN
Cardiovascular diseases (CVDs) remain major causes of global mortality in the world. Genetic approaches have succeeded in the discovery of the molecular basis of an increasing number of cardiac diseases. Genome-editing strategies are one of the most effective methods for assisting therapeutic approaches. Potential therapeutic methods of correcting disease-causing mutations or of knocking out specific genes as approaches for the prevention of CVDs have gained substantial attention using genome-editing techniques. Recently, the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system has become the most widely used genome-editing technology in molecular biology due to its benefits such as simple design, high efficiency, good repeatability, short cycle, and cost-effectiveness. In the present review, we discuss the possibilities of applying the CRISPR/Cas9 genome-editing tool in the CVDs.
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Mounting evidence suggests that the tissue inhibitor of metalloproteinases-2 (TIMP2) can reduce tumor burden and metastasis. However, the demonstration of such anti-tumor activity and associated mechanisms using in vivo tumor models is lacking. The effects of a Timp2 functional mutation and administration of recombinant TIMP2 were examined in both orthotopic and heterotopic murine models of lung cancer using C57Bl/6 syngeneic Lewis Lung 2-luciferase 2 cells (LL2-luc2) cells. Mice harboring a functional mutation of TIMP2 (mT2) display markedly increased primary lung tumor growth, increased mortality, enriched vasculature, and enhanced infiltration of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both mutant and wild-type (wt) mice. Comparison of transcriptional profiles of lung tissues from tumor-free, wt versus mT2 mice reveals only minor changes. However, lung tumor-bearing mice of both genotypes demonstrate significant genotype-dependent changes in gene expression following treatment with TIMP. In tumor-bearing wt mice, TIMP2 treatment reduced the expression of upstream oncogenic mediators, whereas treatment of mT2 mice resulted in an immunomodulatory phenotype. A heterotopic subcutaneous model generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2 significantly downregulates the expression of heat shock proteins, suggesting a reduction of cell-stress responses. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. Our findings show that TIMP2 treatment demonstrates significant potential as an adjuvant in the treatment of NSCLC.