A phase III, multicenter, randomized controlled trial of preoperative versus postoperative stereotactic radiosurgery for patients with surgically resectable brain metastases.

BACKGROUND: Postoperative stereotactic radiosurgery (SRS) is a standard management option for patients with resected brain metastases. Preoperative SRS may have certain advantages compared to postoperative SRS, including less uncertainty in delineation of the intact tumor compared to the postoperative resection cavity, reduced rate of leptomeningeal dissemination postoperatively, and a lower risk of radiation necrosis. The recently published ASCO-SNO-ASTRO consensus statement provides no recommendation for the preferred sequencing of radiotherapy and surgery for patients receiving both treatments for their brain metastases. METHODS: This multicenter, randomized controlled trial aims to recruit 88 patients with resectable brain metastases over an estimated three-year period. Patients with ten or fewer brain metastases with at least one resectable, fulfilling inclusion criteria will be randomized to postoperative SRS (standard arm) or preoperative SRS (investigational arm) in a 1:1 ratio. Randomization will be stratified by age (< 60 versus ≥60 years), histology (melanoma/renal cell carcinoma/sarcoma versus other), and number of metastases (one versus 2-10). In the standard arm, postoperative SRS will be delivered within 3 weeks of surgery, and all unresected metastases will receive primary SRS. In the investigational arm, enrolled patients will receive SRS of all brain metastases followed by surgery of resectable metastases within one week of SRS. In either arm, single fraction or hypofractionated SRS in three or five fractions is permitted. The primary endpoint is to assess local control at 12 months in both arms. Secondary endpoints include local control at other time points, regional/distant brain recurrence rates, leptomeningeal recurrence rates, overall survival, neurocognitive outcomes, and adverse radiation events including radiation necrosis rates in both arms. DISCUSSION: This trial addresses the unanswered question of the optimal sequencing of surgery and SRS in the management of patients with resectable brain metastases. No randomized data comparing preoperative and postoperative SRS for patients with brain metastases has been published to date. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04474925; registered on July 17, 2020. Protocol version 1.0 (January 31, 2020). SPONSOR: Alberta Health Services, Edmonton, Canada (Samir Patel, MD).

Symmetry induced phonon renormalization in few layers of 2H-MoTe2 transistors: Raman and first-principles studies.

Understanding of electron-phonon coupling (EPC) in two-dimensional (2D) materials manifesting as phonon renormalization is essential to their possible applications in nanoelectronics. Here we report in situ Raman measurements of electrochemically top-gated 2, 3 and 7 layered 2H-MoTe2 channel based field-effect transistors. While the [Formula: see text] and B2g phonon modes exhibit frequency softening and linewidth broadening with hole doping concentration (p) up to ∼2.3 × 1013/cm2, A1g shows relatively small frequency hardening and linewidth sharpening. The dependence of frequency renormalization of the [Formula: see text] mode on the number of layers in these 2D crystals confirms that hole doping occurs primarily in the top two layers, in agreement with recent predictions. We present first-principles density functional theory analysis of bilayer MoTe2 that qualitatively captures our observations, and explain that a relatively stronger coupling of holes with [Formula: see text] or B2g modes as compared with the A1g mode originates from the in-plane orbital character and symmetry of the states at valence band maximum. The contrast between the manifestation of EPC in monolayer MoS2 and those observed here in a few-layered MoTe2 demonstrates the role of the symmetry of phonons and electronic states in determining the EPC in these isostructural systems.

Cannabinoid Signaling in Cancer.

The family of chemical structures that interact with a cannabinoid receptor are broadly termed cannabinoids. Traditionally known for their psychotropic effects and their use as palliative medicine in cancer, cannabinoids are very versatile and are known to interact with several orphan receptors besides cannabinoid receptors (CBR) in the body. Recent studies have shown that several key pathways involved in cell growth, differentiation and, even metabolism and apoptosis crosstalk with cannabinoid signaling. Several of these pathways including AKT, EGFR, and mTOR are known to contribute to tumor development and metastasis, and cannabinoids may reverse their effects, thereby by inducing apoptosis, autophagy and modulating the immune system. In this book chapter, we explore how cannabinoids regulate diverse signaling mechanisms in cancer and immune cells within the tumor microenvironment and whether they impart a therapeutic effect. We also provide some important insight into the role of cannabinoids in cellular and whole body metabolism in the context of tumor inhibition. Finally, we highlight recent and ongoing clinical trials that include cannabinoids as a therapeutic strategy and several combinational approaches towards novel therapeutic opportunities in several invasive cancer conditions.

Heat Killed Attenuated Leishmania Induces Apoptosis of HepG2 Cells Through ROS Mediated p53 Dependent Mitochondrial Pathway.

BACKGROUND/AIMS: Cytotoxic effect of attenuated Leishmania on liver cancer cells by inducing ROS generation. METHODS: Spectrophotometric study to analyze cell death and levels of different active caspases. Flow cytometric study was done to analyze apoptosis induction and ROS generation and levels of different protein. Western blot analysis was performed to study the levels of protein. Confocal microscopy was done to ascertain the expression of different apoptotic markers. RESULTS: We have now observed that attenuated Leishmania donovani UR6 also has potentiality towards growth inhibition of HepG2 cells and investigated the mechanism of action. The effect is associated with increased DNA fragmentation, rise in number of annexinV positive cells, and cell cycle arrest at G1 phase. The detection of unregulated levels of active PARP, cleaved caspases 3 and 9, cytosolic cytochrome C, Bax, and Bad, along with the observed downregulation of Bcl-2 and loss of mitochondrial membrane potential suggested the involvement of mitochondrial pathway. Enhanced ROS and p53 levels regulate the apoptosis of HepG2 cells. NAC was found to inhibit p53 production but PFT-α has no effect on ROS generation. In conclusion, Leishmania donovani UR6 efficiently induces apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway. CONCLUSION: It has been reported earlier that some parasites show prominent cytotoxic effect and prevent tumor growth. From our study we found that Leishmania donovani UR6 efficiently induced apoptosis in HepG2 cells through ROS mediated p53 dependent mitochondrial pathway. This study has rejuvenated the age old idea of bio-therapy.

Antineoplastic impact of leishmanial sphingolipid in tumour growth with regulation of angiogenic event and inflammatory response.

Very often conventional therapy, i.e. chemotherapeutic treatment, develops resistance in cancer cells and fails to be effective against disease states. An alternative strategy or a new entity may resolve the problem. Interestingly, the microbial world has begun to be explored in medicinal research as a potential new source to deliver bio-active molecules such as sphingolipids for efficacious cancer treatment. A sphingolipid of microbial origin, especially from Leishmania donovani (LSPL), is a novel entity which may exert anti-cancer activity by regulating cellular growth. The present study reveals that among a range of cancer cells evaluated, LSPL-1 (a component of LSPL) reduces cell viability, annexin exposures and arrests cell cycle in B16F10 cells in a concentration and time dependent manner. Flowcytometric analysis showed that it alters mitochondrial membrane potential and generates a number of ROS positive melanoma cells. It activates p53 at serine anchor region via up-regulation of p21 subunit along with PUMA and NOXA. It also exerts activity in vivo by reducing tumor micro vessel and mitotic index while simultaneously improving the survival rate. The inflammatory responses including elevated level of cytokine-chemokine and increased expression of PCNA and F480 are subdued by LSPL-1 treatment in tumour bearing mice. Besides, it reduces the metastatic outburst of angiogenic factors like VEGF, Ang-2, and CD34 through the involvement of several growth promoting factors. These findings indicate that LSPL-1 may be explored as a potent entity against melanoma growth and the associated angiogenic promotion.

Leishmanial sphingolipid induces apoptosis in Sarcoma 180 cancer cells through regulation of tumour growth via angiogenic switchover.

Sphingolipids are membrane and intracellular lipids that typically modulate cellular processes to cause cell death. Exogenous administration of sphingolipids may cause restriction of tumour growth and several alternative strategies are being used to control the cell growth. The microbes, their cellular component(s) or metabolites like DHA, EPA and also FTY720 have been employed as new therapeutic entities to regulate the disease condition. The therapeutic efficacy of lipids from Leishmania donovani in rheumatoid arthritis and also in sepsis condition associated with inflammatory diseases is well established. In this study, we explored the apoptotic effect of LSPL-1 (leishmanial sphingolipid-1) in Sarcoma 180 cells towards the regulation of tumour growth. The study using a panel of cancer cell lines revealed that LSPL-1 induces cell death in Sarcoma 180. The apoptotic changes were assessed by annexin exposure and DNA content analysis using flow cytometry. LSPL-1 appears to activate several pro- and anti-apoptotic molecules through reactive oxygen species (ROS) generation and also caspase activation, as determined by Western blot and ELISA analyses. Simultaneously, it may improve the survival rate of mice bearing tumour induced by Sarcoma 180 cells, with pathological changes. LSPL-1 may also suppress the cancer-associated inflammatory responses with the expression of matrix metalloproteinase having inhibitory role. It may regulate several angiogenic factors including VEGF, Ang-2 and CD34 in angiogenic events generated in Sarcoma 180 cell-induced tumour. These studies underline the significance of anti-neoplastic potential of LSPL-1 through apoptosis induction and abrogation of angiogenic responses in Sarcoma 180 cell-associated tumour.

A molecular dynamics study of model SI clathrate hydrates: the effect of guest size and guest-water interaction on decomposition kinetics.

One of the options suggested for methane recovery from natural gas hydrates is molecular replacement of methane by suitable guests like CO2 and N2. This approach has been found to be feasible through many experimental and molecular dynamics simulation studies. However, the long term stability of the resultant hydrate needs to be evaluated; the decomposition rate of these hydrates is expected to depend on the interaction between these guest and water molecules. In this work, molecular dynamics simulation has been performed to illustrate the effect of guest molecules with different sizes and interaction strengths with water on structure I (SI) hydrate decomposition and hence the stability. The van der Waals interaction between water of hydrate cages and guest molecules is defined by Lennard Jones potential parameters. A wide range of parameter spaces has been scanned by changing the guest molecules in the SI hydrate, which acts as a model gas for occupying the small and large cages of the SI hydrate. All atomistic simulation results show that the stability of the hydrate is sensitive to the size and interaction of the guest molecules with hydrate water. The increase in the interaction of guest molecules with water stabilizes the hydrate, which in turn shows a slower rate of hydrate decomposition. Similarly guest molecules with a reasonably small (similar to Helium) or large size increase the decomposition rate. The results were also analyzed by calculating the structural order parameter to understand the dynamics of crystal structure and correlated with the release rate of guest molecules from the solid hydrate phase. The results have been explained based on the calculation of potential energies felt by guest molecules in amorphous water, hydrate bulk and hydrate-water interface regions.

Lipid isolated from a Leishmania donovani strain reduces Escherichia coli induced sepsis in mice through inhibition of inflammatory responses.

Sepsis is the reflection of systemic immune response that manifests in the sequential inflammatory process in presence of infection. This may occur as a result of gram-negative bacterial sepsis including Escherichia coli infection that gives rise to excessive production of inflammatory mediators and causes severe tissue injuries. We have reported earlier that the lipid of attenuated Leishmania donovani suppresses the inflammatory responses in arthritis patients. Using heat killed E. coli stimulated macrophages, we have now investigated the effect of leishmanial total lipid (LTL) isolated from Leishmania donovani (MHO/IN/1978/UR6) for amelioration of the inflammatory mediators and transcriptional factor with suppression of TLR4-CD14 expression. To evaluate the in vivo effect, E. coli induced murine sepsis model was used focusing on the changes in different parameter(s) of lung injury caused by sepsis, namely, edema, vascular permeability, and pathophysiology, and the status of different cytokine-chemokine(s) and adhesion molecule(s). Due to the effect of LTL, E. coli induced inflammatory cytokine-chemokine(s) levels were significantly reduced in serum and bronchoalveolar lavage fluid simultaneously. LTL also improved the lung injury and suppressed the cell adhesion molecules in lung tissue. These findings indicate that LTL may prove to be a potential anti-inflammatory agent and provide protection against gram-negative bacterial sepsis with pulmonary impairment.

Reticular synthesis of two-dimensional ionic covalent organic networks as metal-free bifunctional electrocatalysts for oxygen reduction and evolution reactions.

Bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) are the heart of metal-air batteries, fuel cells, and other energy storage systems. Here, we report a series of a novel class of redox-active viologen-based ionic covalent organic networks (vCONs) which are directly used as metal-free bifunctional electrocatalysts towards ORR and OER applications. These vCONs (named vGC, vGAC, vMEL and vBPDP) were synthesized by the well-known Zincke reaction. The installation of redox-active viologen moieties among the extended covalent organic architectures played a crucial role for exceptional acid/base stability, as well as bifunctional ORR and OER activities, confirmed by the cyclic voltammetry (CV) curves. Among all of them, vBPDP showed high ORR efficiency with a half-wave potential of 0.72 V against a reversible hydrogen electrode (RHE) in 1 M KOH electrolyte. In contrast, vMEL demonstrated high OER activity with an overpotential of 320 mV at a current density of 10 mAcm-2 and a Tafel slope of 109.4 mV dec-1 in 1 M KOH electrolyte solution. This work is exceptional and unique in terms of directly used pristine ionic covalent organic networks that are used as bifunctional (ORR and OER) electrocatalysts without adding any metals or conductive materials.

Hydroxide Ion Conduction through Viologen-Based Covalent Organic Frameworks (vCOFs): An Approach toward the Advancement.

Alkaline fuel cells rely on the movement of hydroxide anions (OH-) for their operation, yet these anions face challenges in efficient conduction due to their limited diffusion coefficient and substantial mass compared to proton (H+) transport. Within the covalent organic framework structure, ordered channels offer a promising solution for the OH- ion transport. Herein, we synthesized a cationic covalent organic framework (vTAPA) via the solvothermal-assisted Zincke reaction. vTAPA showcases excellent stability in harsh basic solution (12 M) and a wide range of pH. This framework facilitates OH- conduction through its one-dimensional network through the anion exchange process. We employed various tertiary ammonium salts (tetramethyl, tetraethyl, and tetrabutyl ammonium hydroxide) to exchange trapped anionic chloride ions inside the vTAPA structure with OH- ions. The density functional theory (DFT) study exhibited that the anion exchange process is very favorable, as the vTAPA framework offers preferable interaction sites for OH- ions. The impact of steric hindrance from these tertiary ammonium salts on the OH- conduction performance was extensively investigated. Butyl@vTAPA exhibited a high OH- ion conductivity of 1.05 × 10-4 S cm-1 at 90 °C under 98% relative humidity (RH). Our uniquely designed cationic covalent organic frameworks (COF) created a platform for a preferential transport network of hydroxide ions, and this is the first report of directly used COFs for hydroxide ion conduction without any vigorous postsynthetic modification.

Effect of corchorusin-D, a saikosaponin like compound, on B16F10 melanoma cells (in vitro and in vivo).

Corchorusin-D (COR-D), isolated from Corchorus acutangulus, was reported to induce apoptosis in leukemic cells. However, no studies concerning its activity on melanoma cells have been reported. We have evaluated its in vitro anti-cancer activity on melanoma cells (B16F10, SK-MEL-28, and A375). The results demonstrate that COR-D showed maximum inhibition of B16F10 cells in vitro. COR-D induced mitochondrial dysfunction and altered the Bax/Bcl-2 ratio with down regulation of pro-caspases 9 and activation of caspase 3 in B16F10 cells, triggering intrinsic pathway of apoptosis. Moreover, it inhibited the in vivo B16F10 tumor growth and increased the survival rate of mice. Greater number of Annexin V-FITC and propidium iodide (PI)-positive tumor cells signified that COR-D induced apoptosis in vivo also. The reduction in tumor growth is well correlated with decreased microvascular density of the tumor cells in treated mice. In conclusion, this study reveals that COR-D-induced mitochondrial dysfunction is responsible for the induction of apoptotic cell death.

Can machine learning models improve early detection of brain metastases using diffusion weighted imaging-based radiomics?

Background: Metastatic complications are a major cause of cancer-related morbidity, with up to 40% of cancer patients experiencing at least one brain metastasis. Earlier detection may significantly improve patient outcomes and overall survival. We investigated machine learning (ML) models for early detection of brain metastases based on diffusion weighted imaging (DWI) radiomics. Methods: Longitudinal diffusion imaging from 116 patients previously treated with stereotactic radiosurgery (SRS) for brain metastases were retrospectively analyzed. Clinical contours from 600 metastases were extracted from radiosurgery planning computed tomography, and rigidly registered to corresponding contrast enhanced-T1 and apparent diffusion coefficient (ADC) maps. Contralateral contours located in healthy brain tissue were used as control. The dataset consisted of (I) radiomic features using ADC maps, (II) radiomic feature change calculated using timepoints before the metastasis manifested on contrast enhanced-T1, (III) primary cancer, and (IV) anatomical location. The dataset was divided into training and internal validation sets using an 80/20 split with stratification. Four classification algorithms [Linear Support Vector Machine (SVM), Random Forest (RF), AdaBoost, and XGBoost] underwent supervised classification training, with contours labeled either 'control' or 'metastasis'. Hyperparameters were optimized towards balanced accuracy. Various model metrics (receiver operating characteristic curve area scores, accuracy, recall, and precision) were calculated to gauge performance. Results: The radiomic and clinical data set, feature engineering, and ML models developed were able to identify metastases with an accuracy of up to 87.7% on the training set, and 85.8% on an unseen test set. XGBoost and RF showed superior accuracy (XGBoost: 0.877±0.021 and 0.833±0.47, RF: 0.823±0.024 and 0.858±0.045) for training and validation sets, respectively. XGBoost and RF also showed strong area under the receiver operating characteristic curve (AUC) performance on the validation set (0.910±0.037 and 0.922±0.034, respectively). AdaBoost performed slightly lower in all metrics. SVM model generalized poorly with the internal validation set. Important features involved changes in radiomics months before manifesting on contrast enhanced-T1. Conclusions: The proposed models using diffusion-based radiomics showed encouraging results in differentiating healthy brain tissue from metastases using clinical imaging data. These findings suggest that longitudinal diffusion imaging and ML may help improve patient care through earlier diagnosis and increased patient monitoring/follow-up. Future work aims to improve model classification metrics, robustness, user-interface, and clinical applicability.

Estimated absolute percentage of biopsied tissue positive for Gleason pattern 4 (eAPP4) in low dose rate prostate brachytherapy: Evaluation of prognostic utility in a large cohort.

PURPOSE: To determine whether a system to estimate Absolute Percentage of Biopsied Tissue Positive for Gleason Pattern 4 (eAPP4) is useful as a prognostication tool for patients with intermediate risk prostate cancer (IR-PCa) undergoing low dose rate prostate brachytherapy. METHODS: 497 patients with IR-PCa and known grade group 2 or 3 disease treated with low dose rate seed brachytherapy (LDR-BT) at a quaternary cancer centre were retrospectively reviewed. Prostate biopsies for each patient included Gleason grading with synoptic reporting that did not include percentage of pattern 4 disease found within the sample. Each core was assigned a grade grouping, however, and that was used with optimized estimates of percentage of pattern four disease to estimate eAPP4. Outcomes including cumulative incidence of recurrence (CIR), treatment of recurrent disease (RRX), and metastasis-free survival (MFS) were then reviewed and the prognostic value of eAPP4 evaluated. RESULTS: 428 (86%) patients had Gleason grade group 2 and 69 (14%) patients had Gleason grade group 3 disease. 230 (46%) patients had National Comprehensive Cancer Network (NCCN) favourable intermediate at baseline, while 267 (54%) of patients had NCCN unfavourable intermediate at baseline. Median follow-up was 7.3 (5.5-9.6) years. eAPP4 was predictive of CIR (p = 0.003), RRX (p = 0.003), or MFS (p = 0.001) events, while Gleason grade grouping alone was not. eAPP4 was strongest as a predictor for MFS when estimates of 30% (grade group 2) and 80% (grade group 3) were used [HR 1.07 (1.03-1.12); p = 0.001]. CONCLUSIONS: eAPP4 was strongly predictive of recurrence and metastasis-free survival in a large cohort of patients receiving LDR-BT treatment for IR-PCa. Treatment of future patients with IR-PCa could include the use of eAPP4 prognostication.

Anticancer potential of 3-(arylideneamino)-2-phenylquinazoline-4(3H)-one derivatives.

Different quinazoline derivatives have showed wide spectrum of pharmacological activities. Some 3-(arylideneamino)-phenylquinazoline-4(3H)-ones have been reported to possess antimicrobial activity. The present study has been undertaken to evaluate the anticancer effect of these quinazolinone derivatives. The quinazolinone derivatives were synthesized as reported earlier. Compounds containing NO(2), OH, OCH(3), or OH and OCH(3) as substituent(s) on the arylideneamino group were named as P(3a), P(3b), P(3c), and P(3d) respectively. Out of these, P(3a) and P(3d) showed better cytotoxic activity than P(3b) and P(3c) on a panel of six cancer cell lines of different origin, namely, B16F10, MiaPaCa-2, HCT116, HeLa, MCF7, and HepG2, though the effect was higher in B16F10, HCT116, and MCF7 cells. P(3a) and P(3d) induced death of B16F10 and HCT116 cells was associated with characteristic apoptotic changes like cell shrinkage, nuclear condensation, DNA fragmentation, and annexin V binding. Also, cell cycle arrest at G1 phase, alteration of caspase-3, caspase-9, Bcl-2 and PARP levels, loss of mitochondrial membrane potential, and enhanced level of cytosolic cytochrome c were observed in treated B16F10 cells. Treatment with multiple doses of P(3a) significantly increased the survival rate of B16F10 tumor bearing BALB/c mice by suppressing the volume of tumor while decreasing microvascular density and mitotic index of the tumor cells.

Exploring the anti-inflammatory activity of a novel 2-phenylquinazoline analog with protection against inflammatory injury.

Inflammation is a protective immune response against harmful stimuli whose long time continuation results in host disease. Quinazolinones are nitrogen containing heterocyclic compounds with wide spectrum of biological activities. The anticancer effect of a 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative was reported earlier. The anti-inflammatory effect of these quinazolinone derivatives has now been examined in endotoxin stimulated macrophages and in different in vivo models of inflammation by measuring the proinflammatory cytokines (TNF-α, IL-1ß and IL-6), mediators NO and NF-κB (by ELISA and western blot), and translocation of the nuclear factor kB (by immunocytochemical analysis). To elucidate the in vivo effect, mice endotoxin model was and the various levels of edema, inflammatory pain and vascular permeability were studied. One of the quinazolinone derivatives showed significant anti-inflammatory activity in stimulated macrophage cells by inhibiting the expression of TNF-α, IL-1ß, IL-6, iNOS, COX-2, p-IκB and NF-κBp65. Significant (P<0.01) improvement was observed in the mortality of endotoxemic mice. The carrageenan and formalin-induced paw edema thicknesses were found to be reduced significantly (P<0.01) along with the reduction of pain, vascular permeability and edema induced by complete Freund's adjuvant (P<0.01). These findings indicate that 3-(arylideneamino)-phenylquinazoline-4(3H)-one derivative as a potential anti-inflammatory agent.

Leishmania donovani infection induce Extracellular signal-regulated kinase ½ (ERK½) mediated lipid droplet generation in macrophages.

Recently unfolded mechanisms showed lipid droplet helps in pathogen survival and paralyzes host immune response. In the present study, we showed the extent of lipid droplet(LD) generation in Leishmania donovani infection, the signaling involved, and their function concerning pathogenicity. RAW 264.7 and J774A.1 cells were used to infect with L. donovani and then flow cytometry and confocal microscopy were used to detect lipid droplet generation and subsequent assays. In this study, we showed that L. donovani AG83 (AG83/MHOM/1983) triggers lipid droplet formation in macrophages in a time-dependent manner. We provide novel insight into the signaling molecules which is responsible for LD accumulation. Interestingly, LPG deficient attenuated Leishmania strain UR6 (UR6/MHOM/1978) failed to fuel LD generation. But inhibition of phagosome maturation drastically stimulates LD accumulation in UR6 infected MΦs. Aspirin treatment in AG83 infected MΦs does not only lower LD load but also favors phagolysosome biogenesis and corrects cytokine balance. Employing strategies to circumvent halt in phagosome maturation using drugs that manipulate lipid droplet generation could be used as a therapeutic tool to resist parasite growth in the early hour of infection.

Doping controlled Fano resonance in bilayer 1T'-ReS2: Raman experiments and first-principles theoretical analysis.

In the bilayer ReS2 channel of a field-effect transistor (FET), we demonstrate using Raman spectroscopy that electron doping (n) results in softening of frequency and broadening of linewidth for the in-plane vibrational modes, leaving the out-of-plane vibrational modes unaffected. The largest change is observed for the in-plane Raman mode at ∼151 cm-1, which also shows doping induced Fano resonance with the Fano parameter 1/q = -0.17 at a doping concentration of ∼3.7 × 1013 cm-2. A quantitative understanding of our results is provided by first-principles density functional theory (DFT), showing that the electron-phonon coupling (EPC) of in-plane modes is stronger than that of out-of-plane modes, and its variation with doping is independent of the layer stacking. The origin of large EPC is traced to 1T to 1T' structural phase transition of ReS2 involving in-plane displacement of atoms whose instability is driven by the nested Fermi surface of the 1T structure. Results are compared with those of the isostructural trilayer ReSe2.

Thickness dependent transition from the 1T' to Weyl semimetal phase in ultrathin MoTe2: electrical transport, noise and Raman studies.

Bulk 1T'-MoTe2 shows a structural phase transition from the 1T' to Weyl semimetallic (WSM) Td phase at ∼240 K. This phase transition and transport properties in the two phases have not been investigated on ultra-thin crystals. Here we report electrical transport, 1/f noise and Raman studies on ultra-thin 1T'-MoTe2 (∼5 to 16 nm thick) field-effect transistor (FETs) devices as a function of temperature. The electrical resistivities for a thickness of 16 nm and 11 nm show maxima at temperatures of 208 K and 178 K, respectively, making a transition from the semiconducting to semi-metallic phase, hitherto not observed in bulk samples. Raman frequencies and linewidths for an 11 nm thick crystal show a change around 178 K, attributed to the additional contribution to the phonon self-energy due to the enhanced electron-phonon interaction in the WSM phase. Furthermore, the resistivity at low temperature shows an upturn below 20 K along with the maximum in the power spectral density of the low frequency 1/f noise. The latter rules out the metal-insulator transition (MIT) being responsible for the upturn of resistivity below 20 K. The low temperature resistivity follows ρ∝ 1/T, changing to ρ∝T with increasing temperature supports electron-electron interaction physics at electron-hole symmetric Weyl nodes below 20 K. These observations will pave the way to unravel the properties of the WSM state in layered ultra-thin van der Waals materials.

Macrophage migration inhibitory factor inhibition as a novel therapeutic approach against triple-negative breast cancer.

Triple-negative breast cancer (TNBC), defined as loss of estrogen, progesterone, and Her2 receptors, is a subtype of highly aggressive breast cancer with worse prognosis and poor survival rate. Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory cytokine aberrantly expressed in many solid tumors and known to promote tumor progression and metastasis. However, its role in TNBC progression and metastasis is unexplored. Here we have shown that in TNBC patients, MIF expression was significantly enriched in the tumor compared to adjacent normal tissue. Using publically available patient datasets, we showed that MIF overexpression correlates with worse survival in TNBC compared to other hormonal status. Orthotopic implantation of TNBC cells into MIF knockout mice showed reduced tumor growth compared to wild-type mice. In addition, we have shown that MIF downregulation inhibits TNBC growth and progression in a syngeneic mouse model. We further showed that CPSI-1306, a small-molecule MIF inhibitor, inhibits the growth of TNBC cells in vitro. Mechanistic studies revealed that CPSI-1306 induces intrinsic apoptosis by alteration in mitochondrial membrane potential, cytochrome c (Cyt c) release, and activation of different caspases. In addition, CPSI-1306 inhibits the activation of cell survival and proliferation-related molecules. CPSI-1306 treatment also reduced the tumor growth and metastasis in orthotopic mouse models of mammary carcinoma. CPSI-1306 treatment of tumor-bearing mice significantly inhibited TNBC growth and pulmonary metastasis in a dose-dependent manner. Histological analysis of xenograft tumors revealed a higher number of apoptotic cells in CPSI-1306-treated tumors compared to vehicle controls. Our studies, for the first time, show that MIF overexpression in TNBC enhances growth and metastasis. Taken together, our results indicate that using small molecular weight MIF inhibitors could be a promising strategy to inhibit TNBC progression and metastasis.

Inhibition of TGF-ß induced lipid droplets switches M2 macrophages to M1 phenotype.

Lipid droplets (LD) are newly characterized dynamic cytoplasmic organelle which is the storehouse of different immunosuppressive cytokines and enzymes like cyclooxygenase and lipoxygenase. Tumors are known to modulate the immune system by immune-editing the microenvironment. Immuno-editing comprises of three steps namely cancer immune-surveillance, tumor dormancy and finally escape leading to tumor development. The latency of the tumor microenvironment is greatly contributed by the M2 polarized macrophages and TGF-ß is a prime culprit. Modulating M2 macrophages to M1 can be a strategy against tumor progression. We found that tumor-conditioned medium or recombinant TGF-ß was efficient to induce LD formation in Raw264.7 cells and the inhibition of LD was associated with the switch of M2 to M1 phenotype involving MEK1/2 axis. Signature molecules of M2 polarized macrophages like CD206 were also downregulated while co-stimulatory molecules like CD80, CD86 were up-regulated along with enhanced surface expression of MHCII when these macrophages were subjected to C75 treatment to reduce the LD formation. The level of pro-inflammatory cytokine, as well as ROS and NO generation, were also increased when TGF-ß treated macrophages were subjected to C75 treatment. This study is probably the first report of this kind and can be used in the future in cancer treatment.