p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.

Design and fabrication of a microelectrode array for studying epileptiform discharges from rodents.

Local field potentials, the extracellular electrical activities from brain regions, provide clinically relevant information about the status of neurophysiological conditions, including epilepsy. In this study, a 13-channel silicon-based single-shank microelectrode array (MEA) was designed and fabricated to record local field potentials (LFPs) from the different depths of a rat's brain. A titanium/gold layer was patterned as electrodes on an oxidized silicon substrate, and silicon dioxide was deposited as a passivation layer. The fabricated array was implanted in the somatosensory cortex of the right hemisphere of an anesthetized rat. The developed MEA was interfaced with an OpenBCI Cyton Daisy Biosensing Board to acquire the local field potentials. The LFPs were acquired at three different neurophysiological conditions, including baseline signals, chemically-induced epileptiform discharges, and recovered baseline signals after anti-epileptic drug (AED) administration. Further, time-frequency analyses were performed on the acquired biopotentials to study the difference in spatiotemporal features. The processed signals and time-frequency analyses clearly distinguish between pre-convulsant and post-AED baselines and evoked epileptiform discharges.

A flexible implantable microelectrode array for recording electrocorticography signals from rodents.

Electrocorticography signals, the intracranial recording of electrical signatures of the brain, are recorded by non-penetrating planar electrode arrays placed on the cortical surface. Flexible electrode arrays minimize the tissue damage upon implantation. This work shows the design and development of a 32-channel flexible microelectrode array to record electrocorticography signals from the rat's brain. The array was fabricated on a biocompatible flexible polyimide substrate. A titanium/gold layer was patterned as electrodes, and a thin polyimide layer was used for insulation. The fabricated microelectrode array was mounted on the exposed somatosensory cortex of the right hemisphere of a rat after craniotomy and incision of the dura. The signals were recorded using OpenBCI Cyton Daisy Biosensing Boards. The array faithfully recorded the baseline electrocorticography signals, the induced epileptic activities after applying a convulsant, and the recovered baseline signals after applying an antiepileptic drug. The signals recorded by such fabricated microelectrode array from anesthetized rats demonstrate its potential to monitor electrical signatures corresponding to epilepsy. Finally, the time-frequency analyses highlight the difference in spatiotemporal features of baseline and evoked epileptic discharges.

Left bundle branch area. A new site for physiological pacing: a pilot study.

Chronic RV pacing may lead to pacing induced cardiomyopathy in some patients and results in a higher risk of development of LV systolic dysfunction, heart failure, mitral regurgitation and atrial fibrillation. His bundle pacing emerged as the most physiologic form of ventricular pacing. However, wide adoption of this technique in routine clinical practice is limited by higher capture thresholds at implant sometimes, lower R wave amplitudes, atrial over sensing and increased risk for late rise in pacing thresholds (resulting in the need for lead revisions). Some recent studies have focused on left bundle branch area pacing as a solution to these problems. In our study, we have compared left bundle branch area pacing (in 22 patients) with conventional right ventricular apical pacing (in 28 patients) who presented to us with conventional indications for pacemaker implantations in term of procedure and fluoroscopy time and short-term lead performance and left ventricular function. The results of our study showed that left bundle branch area pacing is associated with shortened QRS duration (22.36 ± 9.36 ms) and better LV function (higher left ventricular ejection fraction 64.00 ± 3.03 vs. 59.73 ± 6.73 with a p value of 0.013 and lower left ventricular diastolic internal diameter 4.58 ± 0.32 vs. 5.23 ± 0.40 cm with a p value of < 0.001) in comparison to right ventricular apical pacing. The total procedure time and fluoroscopy time was similar (63.15 ± 7.02 vs. 55.15 ± 6.16 min, p value 0.142 and 6.08 ± 1.42 vs. 5.06 ± 1.30 min, p value 0.332 respectively) in left bundle branch area pacing group. The results of this study indicate that left bundle branch area pacing may be an option for physiological pacing in patients requiring a high percentage of ventricular pacing.

Feasibility of RA-LV pacing in patients with symptomatic left bundle branch block: a pilot study.

Several studies have reported the adverse effects of right ventricular apical pacing. Permanent His bundle pacing is proved to be the most physiological. But it can be technically difficult sometimes. One recent large multicenter randomized trial showed that pacing from left ventricular apex or mid-lateral wall has the greatest potential to prevent pacing-induced reduction of cardiac pump function (by maintaining left ventricular mechanical synchrony) and, therefore, can be considered as physiological site. In our study, we have wanted to see the outcome of left ventricular pacing through coronary sinus branch with active fixation bipolar lead as a routine pacing technique in patients with symptomatic left bundle branch block. In our study we have recruited 27 patients for left ventricular pacing through coronary sinus branch (as done in cardiac resynchronization therapy) with active fixation bipolar lead and 33 patients for right ventricular apical pacing (control) and compared left ventricular pacing with right ventricular apical pacing in patients with history of syncope with left bundle branch block in baseline electrocardiography who presented with atrio-ventricular block or prolonged HV interval (≥ 70 ms) on electrophysiology study in term of procedure and fluoroscopy time and short-term lead performance and left ventricular function. The results of our study showed that left ventricular pacing through a tributary of coronary sinus is associated with shortened QRS duration (21.10 ± 3.92 ms) and better LV function (higher left ventricular ejection fraction 64.00 ± 3.03 vs. 59.73 ± 6.73 and lower left ventricular diastolic internal diameter 4.58 ± 0.32 vs. 5.23 ± 0.40 cm) in comparison to right ventricular apical pacing. However, the total procedure time and fluoroscopy time was significantly higher (73.75 ± 11.02 vs. 63.32 ± 6.06 min and 7.08 ± 1.48 vs. 5.02 ± 1.39 min, respectively) in left ventricular pacing group. The results of this study indicate that transvenous left ventricular epicardial pacing may be an option for physiological pacing in patients with symptomatic left bundle branch block.

Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach.

Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of "client" proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.

HSP90 inhibitors in lung cancer: promise still unfulfilled.

Despite recent advances in the treatment of lung cancer, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the United States and worldwide, with a 5-year survival rate of less than 17%. Analysis of the molecular drivers of NSCLC led to the recognition that NSCLC is a collection of distinct, molecularly driven neoplasms. Several subsets of NSCLC with clinical relevance to targeted therapies are defined based on alterations in EGFR, ALK, and other key oncogenic drivers. However, for many oncogenic drivers-such as mutant KRAS-targeted therapies are lacking. Heat shock protein 90 (HSP90) is an adenosine triphosphate (ATP)-dependent molecular chaperone that is critically required for the stability of its clientele, many of which are driver oncoproteins. Therefore, HSP90 inhibitors could prove to be an effective and alternate approach to treat patients with NSCLC that has a specific molecular background or that has acquired resistance to other drugs. Over the last 2 decades, several HSP90 inhibitors have been developed that produced promising preclinical and clinical results. The quest is far from over, however. In this review, we discuss the development and the preclinical and clinical profiles of some of the HSP90 inhibitors that may help to improve the targeted treatment of NSCLC.

Commitment to nutritional endoderm in Eleutherodactylus coqui involves altered nodal signaling and global transcriptional repression.

The vegetal cells of a Xenopus laevis embryo commit to mesendoderm via the Nodal-signaling pathway. In the direct developing frog Eleutherodactylus coqui, mesendoderm is specified at the marginal zone of the early gastrula, and vegetal core cells transform into nutritional endoderm. Nutritional endoderm, a novel tissue, consists of transient, yolky cells that provide nutrition but remain undifferentiated. We report a dual regulation for the generation of nutritional endoderm. First, differential expressions of the Nodal-signal transducers Smad2 and Smad4 were observed during early gastrulation between the marginal zone and the vegetal core cells. Although EcSmad2 RNA as well as total and activated Smad2 protein were detected in the vegetal core, Smad4 protein was expressed less in vegetal core during early gastrulation. Only 12% and 50% of vegetal core cells were positive for nuclear Smad2 and Smad4 signals respectively compared to 100% of marginal zone cells. These results suggest a signaling disruption in the vegetal core. Second, vegetal core cells were transcriptionally repressed. At the blastula stage, both marginal zone and vegetal core cells were transcriptionally silent, but during early gastrulation, only marginal zone cells became transcriptionally active. This indicates the occurrence of a mid-blastula transition in the marginal zone by early gastrulation, but global transcriptional repression persisted in the vegetal core and its derivative, nutritional endoderm, throughout development. We have described a novel mechanism, which prevents differentiation of the vegetal core through differential Nodal-signaling and global transcriptional repression.

Parametric investigation of ultrashort pulsed laser surface texturing on aluminium alloy 7075 for hydrophobicity enhancement.

Hydrophobicity plays a pivotal role in mitigating surface fouling, corrosion, and icing in critical marine and aerospace environments. By employing ultrafast laser texturing, the characteristic properties of a material's surface can be modified. This work investigates the potential of an advanced ultrafast laser texturing manufacturing process to enhance the hydrophobicity of aluminium alloy 7075. The surface properties were characterized using goniometry, 3D profilometry, SEM, and XPS analysis. The findings from this study show that the laser process parameters play a crucial role in the manufacturing of the required surface structures. Numerical optimization with response surface optimization was conducted to maximize the contact angle on these surfaces. The maximum water contact angle achieved was 142º, with an average height roughness (Sa) of 0.87 ± 0.075 µm, maximum height roughness (Sz) of 19.4 ± 2.12 µm, and texture aspect ratio of 0.042. This sample was manufactured with the process parameters of 3W laser power, 0.08 mm hatch distance, and a 3 mm/s scan speed. This study highlights the importance of laser process parameters in the manufacturing of the required surface structures and presents a parametric modeling approach that can be used to optimize the laser process parameters to obtain a specific surface morphology and hydrophobicity. Supplementary Information: The online version contains supplementary material available at 10.1007/s00170-024-12971-8.

Harmonic to anharmonic tuning of moiré potential leading to unconventional Stark effect and giant dipolar repulsion in WS2/WSe2 heterobilayer.

Excitonic states trapped in harmonic moiré wells of twisted heterobilayers is an intriguing testbed for exploring many-body physics. However, the moiré potential is primarily governed by the twist angle, and its dynamic tuning remains a challenge. Here we demonstrate anharmonic tuning of moiré potential in a WS2/WSe2 heterobilayer through gate voltage and optical power. A gate voltage can result in a local in-plane perturbing field with odd parity around the high-symmetry points. This allows us to simultaneously observe the first (linear) and second (parabolic) order Stark shift for the ground state and first excited state, respectively, of the moiré trapped exciton - an effect opposite to conventional quantum-confined Stark shift. Depending on the degree of confinement, these excitons exhibit up to twenty-fold gate-tunability in the lifetime (100 to 5 ns). Also, exciton localization dependent dipolar repulsion leads to an optical power-induced blueshift of ~ 1 meV/µW - a five-fold enhancement over previous reports.

Transfer of laparoscopic radical prostatectomy skills from bench model to animal model: a prospective, single-blind, randomized, controlled study.

PURPOSE: Learning laparoscopic urethrovesical anastomosis is a crucial step in laparoscopic radical prostatectomy. Previously we noted that practice on a low fidelity urethrovesical model was more effective for trainees than basic suturing drills on a foam pad when learning laparoscopic urethrovesical anastomosis skills. We evaluated learner transfer of skills, specifically whether skills learned on the urethrovesical model would transfer to a high fidelity, live animal model. MATERIALS AND METHODS: A total of 28 senior residents, fellows and staff surgeons in urology, general surgery and gynecology were randomized to 2 hours of laparoscopic urethrovesical anastomosis training on a urethrovesical model (group 1) or to basic laparoscopic suturing and knot tying on foam pads (group 2). All participants then performed timed laparoscopic urethrovesical anastomosis on anesthetized female pigs. A blinded urologist scored subject videotaped performance using checklist, global rating scale and end product rating scores. RESULTS: Group 1 was significantly more adept than group 2 at the laparoscopic urethrovesical anastomosis pig task when measured by the checklist, global rating scale and end product rating (each p <0.05). Time to completion was similar in the 2 groups. No statistically significant difference was noted in global rating scale and checklist scores for laparoscopic urethrovesical anastomosis performed on the urethrovesical model vs the pig. CONCLUSIONS: Training on a urethrovesical model is superior to training with basic laparoscopic suturing on a foam pad for performing laparoscopic urethrovesical anastomosis skills on an anesthetized female pig. Skills learned on a urethrovesical model transfer to a high fidelity, live animal model.

Highly Nonlinear Biexcitonic Photocurrent from Ultrafast Interlayer Charge Transfer.

Strong Coulomb interactions in monolayer semiconductors allow them to host optically active large many-body states, such as the five-particle state, charged biexciton. Strong nonlinear light absorption by the charged biexciton under spectral resonance, coupled with its charged nature, makes it intriguing for nonlinear photodetection─an area that is hitherto unexplored. Using the high built-in vertical electric field in an asymmetrically designed few-layer graphene encapsulated 1L-WS2 heterostructure, here we report a large, highly nonlinear photocurrent arising from the strong absorption by two charged biexciton species under zero external bias (self-powered mode). Time-resolved measurement reveals that the generated charged biexcitons transfer to the few-layer graphene in a time scale of sub-5 ps, indicating an ultrafast intrinsic limit of the photoresponse. By using single- and two-color photoluminescence excitation spectroscopy, we show that the two biexcitonic peaks originate from bright-dark and bright-bright exciton-trion combinations. Such innate nonlinearity in the photocurrent due to its biexcitonic origin, coupled with the ultrafast response due to swift interlayer charge transfer, exemplifies the promise of manipulating many-body effects in monolayers toward viable optoelectronic applications.

Assessment of cardiac function in children by strain imaging and its correlation with conventional echocardiographic parameter.

Background: The objectives of this study were to find out of normal reference value for age-dependent longitudinal strain values in children and find its correlation with conventional echocardiographic parameters. Methods: In total, 100 healthy normal children aged between 2 and 15 years were enrolled and divided into three age groups, namely, 2-5 years, 5-10 years, and 10-15 years. Using the GE Vivid 7 ultrasound platform with 4 or 7 MHz probes, both LV and RV global longitudinal strains and conventional echocardiographic parameters were acquired. Results: In normal healthy children, left ventricular GLS values were -20.10 to -19.68 (mean: -19.89), -21.93 to -21.02 (mean: -21.48), and -20.87 to -20.41 (mean: -20.64)) in children aged 2-5 years, 5-10 years, and 10-15 years and right ventricular GLS values were -16.80 to -16.44 (mean: -16.62), -27.85 to -27.27 (mean: -27.56), -28.44 to -27.93 (mean: -28.19) in the above three groups, respectively. No significant increase was noted in the left ventricular strain value from basal to the apical segment from age group 2 years to 15 years and no gender differences were seen. None of the conventional echocardiographic parameters commonly used to assess the left or right ventricular systolic function had a significant correlation with LVGLS and RVGLS. Conclusions: The mean LVGLS values were -19.89, -21.48, and -20.64 and RVGLS were -16.62, -27.56, and -28.19 in healthy normal children aged 2-5 years, 5-10 years, and 10-15 years, respectively, and conventional echocardiographic parameters did not have any significant correlation with these values.

Pressure-Induced Enhanced Optical Absorption in Sulvanite Compound Cu3TaX4 (X = S, Se, and Te): An ab Initio Study.

Ab initio study on the family of ternary copper chalcogenides Cu3TaX4 (X = S, Se, and Te) is performed to investigate the suitability of these compounds to applications as photovoltaic absorber materials. The density functional theory based full potential linearized augmented plane wave method (FP-LAPW method) is employed for computational purposes. The electronic structure and optical properties are determined including electron-electron interaction and spin-orbit coupling (SOC), within the generalized gradient approximation plus Hubbard U (GGA+U) and GGA+U+SOC approximation. The large optical band gaps of Cu3TaS4 and Cu3TaSe4 considered ineffective for absorber materials, and also the hole effective mass has been modulated through applied pressure. These materials show extreme resistance to external pressure, and are found to be stable up to a pressure range of 10 GPa, investigated using phonon dispersion calculations. The observed optical properties and the absorption coefficients within the visible-light spectrum make these compounds promising materials for photovoltaic applications. The calculated energy and optical band gaps are consistent with the available literature and are compared with the experimental results where available.

Management of obstetric hemorrhage.

Major obstetric hemorrhage is an extremely challenging obstetric emergency associated with significant morbidity and mortality. Pharmacological treatment of uterine atony has not altered much in recent years apart from the increasing use ofmisoprostol, although controversy surrounds its advantages over other uterotonics. Placenta accreta is becoming more common, a sequel to the rising caesarean section rate. Interventional radiology may reduce blood loss in these cases. Uterine compression sutures, intrauterine tamponade balloons and cell salvage have been introduced in the last decade.

Assessing the surgical decision making abilities of novice and proficient urologists.

PURPOSE: We examined whether the Surgical Decision Making Rating Scale can measure a difference in surgical judgment among urologists at various levels of training. MATERIALS AND METHODS: A total of 25 medical students, urology residents and staff urologists viewed clips from 8 select urological procedures and verbalized their thought processes. The clips were ordered in increasing complexity from lower level tasks (catheterization and cystoscopy) to more advanced procedures (laser lithotripsy, and open and laparoscopic prostatectomy and nephrectomy). Performance was transcribed and blindly rated using the previously validated rating scale. Subjects were also asked to self-evaluate their performance using this scale. RESULTS: Overall the rating scale distinguished the training level across knowledge domains (anatomy and management of the current task) and judgment domains (avoiding complications, higher reasoning and immediate surgical planning). The mean score across all training levels was 112 of 200 (range 51 to 161). Scale performance showed a significant correlation with seniority (rho = 0.96, p <0.05). This trend persisted when performance was analyzed separately for knowledge and judgment domain elements (rho = 0.95 and 0.96, respectively, each p <0.05). Self-evaluation correlated well with blinded evaluation across all levels of training (rho = 0.87, p = 0.01). CONCLUSIONS: The Surgical Decision Making Rating Scale can reliably detect differences in knowledge and surgical judgment among medical students, urology residents and staff urologists. This tool has potential applications for evaluating trainees and determining subjects with proficient decision making abilities. It also shows a significant correlation between self-rated performance and blinded evaluation.

Futuristic medical implants using bioresorbable materials and devices.

Implantable medical devices have been used for real-time monitoring of physical parameters (temperature, pressure and biopotentials), sustained drug release, cardiovascular and pulmonary stents and other clinical applications. Several biocompatible materials (titanium and its alloys, aluminium, cobalt-alloys, stainless steel, poly-ethylene, polyurethanes, polyglycolide and polylactides) have been commercially used for fabricating implantable devices. However, these devices require retrieval operations after a certain period. Bioresorbable materials disintegrate gradually in vivo and their derivatives get absorbed completely in the body fluid with no residue and with minimal toxic effects, thus, eliminating the need for retrieval operations. In this article, state-of-the-art advances in materials, fabrication techniques and clinical applications of bioresorbable implantable devices are reviewed. We first discuss the bioresorbable materials (e.g., magnesium, molybdenum, tungsten, silicon, germanium, silicon dioxide, silicon nitride, silk and synthetic polymers) used in the fabrication of implantable devices. Later, an overview of processes to fabricate pressure, temperature, electrical and chemical sensors are discussed, followed by their applications as implantable devices in biomedical engineering.

Strong Single- and Two-Photon Luminescence Enhancement by Nonradiative Energy Transfer across Layered Heterostructure.

The strong light-matter interaction in monolayer transition metal dichalcogenides (TMDs) is promising for nanoscale optoelectronics with their direct band gap nature and the ultrafast radiative decay of the strongly bound excitons these materials host. However, the impeded amount of light absorption imposed by the ultrathin nature of the monolayers impairs their viability in photonic applications. Using a layered heterostructure of a monolayer TMD stacked on top of strongly absorbing, nonluminescent, multilayer SnSe2, we show that both single-photon and two-photon luminescence from the TMD monolayer can be enhanced by a factor of 14 and 7.5, respectively. This is enabled through interlayer dipole-dipole coupling induced nonradiative Förster resonance energy transfer (FRET) from SnSe2 underneath, which acts as a scavenger of the light unabsorbed by the monolayer TMD. The design strategy exploits the near-resonance between the direct energy gap of SnSe2 and the excitonic gap of monolayer TMD, the smallest possible separation between donor and acceptor facilitated by van der Waals heterojunction, and the in-plane orientation of dipoles in these layered materials. The FRET-driven uniform single- and two-photon luminescence enhancement over the entire junction area is advantageous over the local enhancement in quantum dot or plasmonic structure integrated 2D layers and is promising for improving quantum efficiency in imaging, optoelectronic, and photonic applications.

Emerging technologies for antibiotic susceptibility testing.

Superbugs such as infectious bacteria pose a great threat to humanity due to an increase in bacterial mortality leading to clinical treatment failure, lengthy hospital stay, intravenous therapy and accretion of bacteraemia. These disease-causing bacteria gain resistance to drugs over time which further complicates the treatment. Monitoring of antibiotic resistance is therefore necessary so that bacterial infectious diseases can be diagnosed rapidly. Antimicrobial susceptibility testing (AST) provides valuable information on the efficacy of antibiotic agents and their dosages for treatment against bacterial infections. In clinical laboratories, most widely used AST methods are disk diffusion, gradient diffusion, broth dilution, or commercially available semi-automated systems. Though these methods are cost-effective and accurate, they are time-consuming, labour-intensive, and require skilled manpower. Recently much attention has been on developing rapid AST techniques to avoid misuse of antibiotics and provide effective treatment. In this review, we have discussed emerging engineering AST techniques with special emphasis on phenotypic AST. These techniques include fluorescence imaging along with computational image processing, surface plasmon resonance, Raman spectra, and laser tweezer as well as micro/nanotechnology-based device such as microfluidics, microdroplets, and microchamber. The mechanical and electrical behaviour of single bacterial cell and bacterial suspension for the study of AST is also discussed.

Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer.

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) have significantly benefited from the use of EGFR tyrosine kinase inhibitors (TKIs). However, long-term efficacy of these therapies is limited due to de novo resistance (~30%) as well as acquired resistance. Epithelial-mesenchymal transition transcription factors (EMT-TFs), have been identified as drivers of EMT-mediated resistance to EGFR TKIs, however, strategies to target EMT-TFs are lacking. As the third generation EGFR TKI, osimertinib, has now been adopted in the first-line setting, the frequency of T790M mutations will significantly decrease in the acquired resistance setting. Previously less common mechanisms of acquired resistance to first generation EGFR TKIs including EMT are now being observed at an increased frequency after osimertinib. Importantly, there are no other FDA approved targeted therapies after progression on osimertinib. Here, we investigated a novel strategy to overcome EGFR TKI resistance through targeting the EMT-TF, TWIST1, in EGFR-mutant NSCLC. We demonstrated that genetic silencing of TWIST1 or treatment with the TWIST1 inhibitor, harmine, resulted in growth inhibition and apoptosis in EGFR-mutant NSCLC. TWIST1 overexpression resulted in erlotinib and osimertinib resistance in EGFR-mutant NSCLC cells. Conversely, genetic and pharmacological inhibition of TWIST1 in EGFR TKI-resistant EGFR-mutant cells increased sensitivity to EGFR TKIs. TWIST1-mediated EGFR TKI resistance was due in part to TWIST1 suppression of transcription of the pro-apoptotic BH3-only gene, BCL2L11 (BIM), by directly binding to BCL2L11 intronic regions and promoter. As such, pan-BCL2 inhibitor treatment overcame TWIST1-mediated EGFR TKI resistance and were more effective in the setting of TWIST1 overexpression. Finally, in a mouse model of autochthonous EGFR-mutant lung cancer, Twist1 overexpression resulted in erlotinib resistance and suppression of erlotinib-induced apoptosis. These studies establish TWIST1 as a driver of resistance to EGFR TKIs and provide rationale for use of TWIST1 inhibitors or BCL2 inhibitors as means to overcome EMT-mediated resistance to EGFR TKIs.