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Cell Dec 2023Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how...
Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU) revival colonic stem cells (revCSCs) to oncogene-driven LRIG1 hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRAS or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRAS collaboratively limit access to revCSCs and disrupt stromal-epithelial communication-trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.
Topics: Cell Differentiation; Oncogenes; Proto-Oncogene Proteins p21(ras); Signal Transduction; Stem Cells; Humans; Animals; Mice; Cell Lineage
PubMed: 38065080
DOI: 10.1016/j.cell.2023.11.004 -
Medicine Jun 2018Controversy exists regarding whether the kinesiology tape application direction affects muscle strength. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Controversy exists regarding whether the kinesiology tape application direction affects muscle strength.
METHODS
Eighteen healthy volunteers (12 men, 6 women) participated. Kinesiology tape was randomly applied to the quadriceps muscles either from origin to insertion or from insertion to origin. A Biodex isokinetic dynamometer was used to measure the peak torque of the quadriceps pre-and post-taping.
RESULTS
There was a significant difference in muscle strength after taping, regardless of the kinesiology tape application direction. There were no significant differences in the peak torque of the quadriceps between the 2 kinesiology tape application directions.
CONCLUSIONS
The application of kinesiology tape application to the rectus femoris, vastus medialis, and vastus lateralis of the quadriceps increased the muscle torque, regardless of the tape application direction. Therefore, to enhance quadriceps strength, we recommend the application of kinesiology tape to 3 of the muscles of the quadriceps (specifically, the rectus femoris, vastus medialis and vastus lateralis), irrespective of the tape application direction.
Topics: Adult; Athletic Tape; Cross-Over Studies; Female; Healthy Volunteers; Humans; Kinesiology, Applied; Male; Muscle Strength; Muscle Strength Dynamometer; Quadriceps Muscle; Torque
PubMed: 29901599
DOI: 10.1097/MD.0000000000011038 -
Cell Dec 2023Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor...
Patient-derived organoids (PDOs) can model personalized therapy responses; however, current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly multiplexed mass cytometry platform to measure post-translational modification (PTM) signaling, DNA damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer-associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment-specific drug responses in thousands of single-cell datasets, we developed "Trellis"-a highly scalable, tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rarer, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate PDO plasticity-shifting proliferative colonic stem cells (proCSCs) to slow-cycling revival colonic stem cells (revCSCs) to protect cancer cells from chemotherapy.
Topics: Humans; Apoptosis; Cancer-Associated Fibroblasts; Organoids; Signal Transduction; Single-Cell Analysis; Drug Evaluation, Preclinical; Algorithms; Stem Cells
PubMed: 38065081
DOI: 10.1016/j.cell.2023.11.005 -
Cancer Cell Jan 2020Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal...
Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.
Topics: Animals; B7-H1 Antigen; Cell Cycle; Cell Line, Tumor; Cytoskeleton; DNA Damage; Drug Resistance, Neoplasm; Female; Humans; Immunotherapy; MAP Kinase Signaling System; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Myosin Type II; Oxidative Stress; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Reactive Oxygen Species; T-Lymphocytes, Regulatory; Treatment Outcome; Tumor Microenvironment; rho-Associated Kinases
PubMed: 31935375
DOI: 10.1016/j.ccell.2019.12.003 -
Proceedings of the National Academy of... Nov 2012Medical tape that provides secure fixation of life-sustaining and -monitoring devices with quick, easy, damage-free removal represents a longstanding unmet medical need...
Medical tape that provides secure fixation of life-sustaining and -monitoring devices with quick, easy, damage-free removal represents a longstanding unmet medical need in neonatal care. During removal of current medical tapes, crack propagation occurs at the adhesive-skin interface, which is also the interface responsible for device fixation. By designing quick-release medical tape to undergo crack propagation between the backing and adhesive layers, we decouple removal and device fixation, enabling dual functionality. We created an ordered adhesive/antiadhesive composite intermediary layer between the medical tape backing and adhesive for which we achieve tunable peel removal force, while maintaining high shear adhesion to secure medical devices. We elucidate the relationship between the spatial ordering of adhesive and antiadhesive regions to create a fully tunable system that achieves strong device fixation and quick, easy, damage-free device removal. We also described ways of neutralizing the residual adhesive on the skin and have observed that thick continuous films of adhesive are easier to remove than the thin islands associated with residual adhesive left by current medical tapes.
Topics: Adhesives; Humans; Materials Testing; Skin
PubMed: 23112196
DOI: 10.1073/pnas.1216071109 -
European Journal of Physical and... Jun 2018Extracorporeal Shock Wave Therapy (ESWT) is effective in the treatment of calcific tendinopathy of the rotator cuff, eliciting an analgesic/anti-inflammatory action and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Extracorporeal Shock Wave Therapy (ESWT) is effective in the treatment of calcific tendinopathy of the rotator cuff, eliciting an analgesic/anti-inflammatory action and promoting tissue regeneration. Kinesio taping (KT), another recently-introduced rehabilitative tool, exerts an analgesic and biomechanical action on joints and muscles. ESWT and KT may have a synergic effect when used in combination, but the effectiveness of the association has not been established.
AIM
The aim of this study was to test if the association of KT with ESWT is superior to ESWT alone in the treatment of rotator cuff calcific tendinopathy.
DESIGN
Randomized controlled trial.
SETTING
Rehabilitation Institute outpatients.
POPULATION
Forty-two patients with rotator cuff calcific tendinopathy were randomly assigned to the experimental group (ESWT+KT, N.=21) or control (ESWT, N.=21).
METHODS
In the experimental group, patients underwent three sessions (once a week for 3 weeks) of ESWT with KT applied at the end of each session. Controls underwent three sessions of ESWT only. All patients were assessed before treatment (T0) and at 1 (T1), 4 (T2) and 12 weeks (T3) after the end of treatment with the following outcome measures: a visual analogue scale (VAS), the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, Subjective Shoulder Rating Questionnaire (SSRQ), and Oxford Shoulder Score (OSS).
RESULTS
Both groups showed significant improvement in all outcome measures, but the time course differed between the two groups. At T1 vs. T0, the improvement was significantly better in ESWT+KT than ESWT on VAS (P=0.007), DASH (P<0.0001) and SSRQ (P=0.0001). Successive improvements at T2 vs. T1 and T3 vs. T2 did not differ significantly between the groups. At the end of follow-up, ESWT+KT still showed significantly greater improvement than ESWT on VAS (P=0.02) and SSRQ (P=0.038).
CONCLUSIONS
KT associated with ESWT seems to improve the recovery in rotator cuff calcific tendinopathy with a faster therapeutic response compared to ESWT only.
CLINICAL REHABILITATION IMPACT
Our results suggest the effectiveness of using KT as adjuvant therapy to ESWT in rotator cuff calcific tendinopathy, through enhancing the short-term analgesic action and the medium- to long-term biological-regenerative effects.
Topics: Adult; Aged; Ambulatory Care; Analysis of Variance; Athletic Tape; Calcinosis; Combined Modality Therapy; Extracorporeal Shockwave Therapy; Female; Humans; Italy; Magnetic Resonance Imaging; Male; Middle Aged; Pain Measurement; Prognosis; Range of Motion, Articular; Rehabilitation Centers; Risk Assessment; Rotator Cuff; Shoulder Joint; Shoulder Pain; Tendinopathy; Treatment Outcome
PubMed: 29185674
DOI: 10.23736/S1973-9087.17.04749-9 -
RSC Advances Aug 2018Skin cancer is the most common form of cancer and is globally rising. Historically, the diagnosis of skin cancers has depended on various conventional techniques which... (Review)
Review
Skin cancer is the most common form of cancer and is globally rising. Historically, the diagnosis of skin cancers has depended on various conventional techniques which are of an invasive manner. A variety of commercial diagnostic tools and auxiliary techniques are available to detect skin cancer. This article explains in detail the principles and approaches involved for non-invasive skin cancer diagnostic methods such as photography, dermoscopy, sonography, confocal microscopy, Raman spectroscopy, fluorescence spectroscopy, terahertz spectroscopy, optical coherence tomography, the multispectral imaging technique, thermography, electrical bio-impedance, tape stripping and computer-aided analysis. The characteristics of an ideal screening test are outlined, and the authors pose several points for clinicians and scientists to consider in the evaluation of current and future studies of skin cancer detection and diagnosis. This comprehensive review critically analyses the literature associated with the field and summarises the recent updates along with their merits and demerits.
PubMed: 35542700
DOI: 10.1039/c8ra04164d -
Journal of Translational Medicine Nov 2018Epicutaneous immunotherapy (EPIT) is a new way of allergen administration that has a high rate of adherence and safety. The aim of this manuscript is to review clinical... (Review)
Review
BACKGROUND
Epicutaneous immunotherapy (EPIT) is a new way of allergen administration that has a high rate of adherence and safety. The aim of this manuscript is to review clinical trials on EPIT for respiratory and food allergies published in the last 10 years, taking into account how different variables (i.e., dose, patch application duration, skin preparation, and efficacy and safety evaluation) have influenced study results.
MAIN BODY
From a review of the literature, we identified eight placebo-controlled, double-blind trials conducted on children and adults, including four studies on grass pollen rhino-conjunctivitis, one on cow's milk allergy and three on peanut allergy. Different methods for skin pre-treatment, such as skin abrasion and tape stripping or stratum corneous hydration by an occlusive system, different endpoints and cumulative allergen doses, and different durations of patch application and tape stripping, were used in the rhino-conjunctivitis studies. A visual analogue system was used for the efficacy evaluation. Several local skin reactions (eczema) and some systemic adverse reactions were reported at higher rates in the active group compared to placebo in one study, but this was not shown by other authors. Local eczema reactions were correlated to the times for applying the tape stripping, while systemic side effects were correlated to the deepness of scraping. In the food allergy trials, differences in the food challenge thresholds, endpoints and allergen sites of the cutaneous patch application influenced the study results. A slight dose-dependent efficacy was found in the peanut allergy studies, which was confirmed by a more significant increase in the following progressive open study. Few adverse events and high adherence in all of the food allergen trials were reported.
CONCLUSIONS
Overall, the EPIT study results, even if they were affected by great heterogeneity among the methodologies applied, have shown not only the high safety and adherence with this kind of immunotherapy but also suggested the possibility for obtaining definitive evidence of the efficacy of EPIT, especially for food allergies.
Topics: Conjunctivitis; Food Hypersensitivity; Humans; Immunotherapy; Rhinitis
PubMed: 30482237
DOI: 10.1186/s12967-018-1701-6 -
Obesity (Silver Spring, Md.) Jun 2022Three-dimensional (3D) imaging systems are increasingly being used in health care settings for quantifying body size and shape. The potential exists to provide similar...
OBJECTIVE
Three-dimensional (3D) imaging systems are increasingly being used in health care settings for quantifying body size and shape. The potential exists to provide similar phenotyping capabilities outside of professional settings using smartphone applications (apps). The current study aim was to compare waist, hip, upper arm, and midthigh circumference measurements acquired by a free downloadable app (MeThreeSixty; Size Stream, Cary, North Carolina) and a conventional 20-camera 3D system (SS20; Size Stream) with those measured with a flexible tape at the same anatomic sites.
METHODS
Fifty-nine adults were scanned with the app and SS20; the same software was used to generate circumference estimates from device-acquired object files that were then compared with reference tape measurements.
RESULTS
The app and SS20 had similar coefficients of variation that were minimally larger than those by the tape (e.g., waist, 0.93%, 0.87%, and 0.06%). Correlations of the app and of SS20 with tape circumferences were all strong (p < 0.001) and similar in magnitude (R s: 0.72-0.93 and 0.78-0.95, respectively); minimally significant (p < 0.05 to p < 0.01) bias was present between both imaging approaches and some tape measurements.
CONCLUSION
These proof-of-concept observations combined with ubiquitous smartphone availability create the possibility of phenotyping adult body size and shape, with important clinical and research implications, on a global scale.
Topics: Anthropometry; Body Size; Mobile Applications; Smartphone
PubMed: 35491718
DOI: 10.1002/oby.23434 -
Scientific Reports Mar 2019There is a great interest in low-cost, versatile microfluidic platforms of which the fabrication processes are rapid, straightforward, and translatable to industrial...
There is a great interest in low-cost, versatile microfluidic platforms of which the fabrication processes are rapid, straightforward, and translatable to industrial mass productions. In addition, it is beneficial for microfluidic devices to be reconfigurable in the field, so that multiple functions can be realized by a minimum number of devices. Here, we present a versatile acrylic-tape platform which allows highly accessible rapid prototyping of microfluidic devices, as well as device reconfiguration to realize different functions. The clean-room-free fabrication and sealing process only requires a laser cutter, acrylic, and tapes and can be done by an untrained person in the field. We experimentally characterized the relationship between the capillary flow speed and the channel height, the latter of which can be well controlled by the fabrication process. Reconfiguration of microfluidic functions was demonstrated on a single acrylic-tape device, thanks to the reversible sealing enabled by functional tapes. Different pumping mechanisms, including on-chip pumps for better portability and syringe pumps for precise fluid control, have been employed for the demonstration of two-phase flow and droplet generation, respectively. The low-cost and versatile acrylic-tape microfluidic devices are promising tools for applications in a wide range of fields, especially for point-of-care biomedical and clinical applications.
PubMed: 30886239
DOI: 10.1038/s41598-019-41208-y