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Breast cancer is the most diagnosed cancer among women. Approximately 15–20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC 50 ) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin β4 (ITGβ4) expression and cancer stem cell properties. ITGβ4 has previously been implicated in promoting “cancer stemness,” which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.

Vibrational polaritons have shown potential in influencing chemical reactions, but the exact mechanism by which they impact vibrational energy redistribution, crucial for rational polariton chemistry design, remains unclear. In this work, we shed light on this aspect by revealing the role of solvent phonon modes in facilitating the energy relaxation process from the polaritons formed of a mode of W(CO) to an IR inactive mode. Ultrafast dynamic measurements indicate that along with the direct relaxation to the dark modes, lower polaritons also transition to an intermediate state, which then subsequently relaxes to the mode. We reason that the intermediate state could correspond to the near-in-energy Raman active mode, which is populated through a phonon scattering process. This proposed mechanism finds support in the observed dependence of the IR-inactive state’s population on the factors influencing phonon density of states, e.g., solvents. The significance of the Raman mode’s involvement emphasizes the importance of non-IR active modes in modifying chemical reactions and ultrafast molecular dynamics.

Hypoxia occurs in 90% of solid tumors and is associated with metastasis and mortality. Breast cancer cells that experience intratumoral hypoxia are 5x more likely to develop lung metastasis in animal models. Using spatial transcriptomics, we determine that hypoxic cells localized in more oxygenated tumor regions (termed ‘post-hypoxic’) retain expression of hypoxia-inducible and NF-kB-regulated genes, even in the oxygen-rich bloodstream. This cellular response is reproduced in vitro under chronic hypoxic conditions followed by reoxygenation. A subset of genes remains increased in reoxygenated cells. MUC1 /MUC1-C is upregulated by both HIF-1α and NF-kB-p65 during chronic hypoxia. Abrogating MUC1 decreases the expression of superoxide dismutase enzymes, causing reactive oxygen species (ROS) production and cell death. A hypoxia-dependent genetic deletion of MUC1, or MUC1-C inhibition by GO-203, increases ROS levels in circulating tumor cells (CTCs), reducing the extent of metastasis. High MUC1 expression in tumor biopsies is associated with recurrence, and MUC1+ CTCs have lower ROS levels than MUC1- CTCs in patient-derived xenograft models. This study demonstrates that therapeutically targeting MUC1-C reduces hypoxia-driven metastasis. Hypoxia is associated with metastasis and mortality. Here, the authors show that intratumoral hypoxia is linked to oxidative stress driving both HIF and NF-kB signaling to sustain a ROS-resistant phenotype that drives metastasis partially via MUC1-C.

Hindfoot, midfoot, and forefoot motion during the stance phase of walking provide insights into the forward progression of the body over the feet via the rocker mechanisms. These segmental motions are affected by walking speed. Increases in walking speed are accomplished by increasing step length and cadence. It is unknown if taking short, medium, and long steps at the same speed would increase hindfoot, midfoot, and forefoot motion similarly to walking speed. We examined effects of different step lengths at the same preferred walking speed on peak forefoot, midfoot, and hindfoot motions related to the foot rockers. Twelve young healthy adults completed five walking trials under three step length conditions in a random order as feet and lower extremity motion were measured via marker positions for the combined Oxford foot and conventional gait models. Peak hindfoot, midfoot, and forefoot joint angles indicating heel, ankle, and forefoot rockers were identified. When walking at the same preferred speed with increase in step length, there were increases in peak hindfoot-tibia plantarflexion angle (p < 0.001; ηp2 = 0.76) in early stance associated with the heel rocker and peak hindfoot-tibia dorsiflexion angle (p = 0.016; ηp2 = 0.39) in midstance associated with ankle rocker. In late stance, the peak hindfoot-tibia plantarflexion angle, forefoot-hindfoot angle, and forefoot-hallux dorsiflexion angle indicating forefoot rocker motion also increased with step length (p < 0.01). When foot kinematics are compared across different individuals or the same individual across different sessions, researchers and clinicians should consider the influence of step length as a contributor to differences in foot kinematics observed.

To the Editor—The COVID-19 pandemic of 2020, caused by a severe coronavirus strain named SARS-CoV-2, and has created shortages of personal protective equipment (PPE).1 The Centers for Disease Control and Prevention (CDC) released a PPE burn rate calculator for hospitals to project future PPE supplies.2 This tool requires that hospital systems have an understanding of daily PPE usage patterns. [...]our calculator does not capture changes in N95 disinfection and N95 use rates, which can be subject to change. Centers for Disease Control and Prevention website. https://www.cdc.gov/coronavirus/2019-ncov/hcp/ppe-strategy/index.html.

Purpose: To determine the pattern of pediatric ocular morbidities in western India. Methods: This was a retrospective longitudinal study that included all consecutive children aged £15 years who presented to the outpatient department of a tertiary eye center for the first time. Patient demographics, best-corrected visual acuity (BCVA), and ocular examination data were compiled. Subgroup analysis was also performed based on age group (years): £5, 5-10, and >10-15. Results: A total of 11,126 eyes of 5563 children were included in the study. The mean age of the study population was 5.15 (±3.32) years with males (57.07%) being predominant. Approximately half of the patients (50.19%) were under the age of 5 years, followed by those aged 5-10 years (45.1%) and >10-15 years (4.71%). Among the study eyes, the BCVA was ³20/60 in 58.57%, indeterminable in 35.16%, and <20/60 in 6.71%. The commonest ocular morbidity noted was refractive error (28.97%) followed by allergic conjunctivitis (7.64%) and strabismus (4.95%) in the total study cohort and also after age stratification. Conclusion: Refractive error, allergic conjunctivitis, and strabismus are the major causes of ocular morbidity in pediatric eyes at a tertiary care center. Planning screening programs at the regional and national levels is crucial to decreasing the burden of eye disorders. These programs also need to have a suitable referral mechanism established and be smoothly connected to primary and secondary health-care centers. This will help to assure quality eye care delivery, while also reducing the strain of overworked tertiary centers.

Background While the use of computer-assisted navigation systems in prosthetic implantation is steadily increasing, its utility in reverse shoulder arthroplasty (RSA) remains unclear. The purpose of this study was to evaluate the clinical utility of an intraoperative navigation system in patients undergoing RSA. Materials and methods Patients undergoing navigated or standard RSA at a single institution between September 2020 and December 2021 were prospectively enrolled. Exclusion criteria included noncompliance with study procedures or humeral fracture. Outcome measures included postoperative version and inclination, range of motion (ROM), complications, and patient-reported outcome measurements (PROMs: American Shoulder and Elbow Surgeons score [ASES], Disabilities of the Arm, Shoulder, and Hand score [DASH], Simple Shoulder Test [SST], and Visual Analog Scale [VAS]) at final follow-up. Results The final cohort contained 16 patients with navigation and 17 with standard RSA at a mean follow-up of 16 months (range 12–18 months). Average age was 72 years (range 66–80 years), 8 male (24%) and 25 female (76%). There were no differences in demographics between groups ( p  > 0.05). At baseline, the navigated group had a greater proportion of Walch B1 and B2 glenoids ( p  = 0.04). There were no differences between groups regarding baseplate type and native/planned/postoperative glenoid version and inclination. In both groups, planned and postoperative versions were not significantly different ( p  = 0.76). Patients who did not have navigation demonstrated significant differences between planned and postoperative inclination ( p  = 0.04), while those with navigation did not ( p  = 0.09). PROM scores did not differ between groups at final follow-up for SST ( p  = 0.64), DASH ( p  = 0.38), ASES ( p  = 0.77), or VAS ( p  = 0.1). No difference in final ROM was found between groups ( p  > 0.05). Over 50% of all screws in both groups were positioned outside the second cortex ( p  = 0.37), albeit with no complications. Conclusions There were no statistically significant differences in ROM, PROMs, and satisfaction between patients receiving computer-navigated and standard RSA at a short-term follow-up. Despite more severe preoperative glenoid erosion in the navigated group, all patients were able to achieve an appropriate neutral axis postoperatively. The cost effectiveness and appropriate use of computer-navigated RSA warrant specific investigation in future studies. Level of evidence: II, prospective cohort study. Trial registration: 9/1/2020 to 12/31/2021.

A reversed-phase HPLC method was designed and validated to serve as a stability-indicating technique for the simultaneous quantification of Teneligliptin, Pioglitazone, and Metformin Hydrochloride in a combined dosage form. This method utilized a Dionex system with a Force scientific C18 column (5μm, 250mm × 4.6mm i.d.) and employed a mobile phase consisting of phosphate buffer (pH 3), methanol, and acetonitrile in a 70:25:05 (%v/v) ratio, with UV detection set at 238nm. The method exhibited linearity across the concentration ranges of 12.5-75 μg/ml for Metformin, 0.5-3.0μg/ml for Teneligliptin, and 0.375-2.25μg/ml for Pioglitazone. It was assessed for system suitability, precision, accuracy, linearity, robustness, and forced degradation, demonstrating its effectiveness in separating the active pharmaceutical ingredients (APIs) from their degradation products and its applicability for analyzing samples of Teneligliptin, Pioglitazone, and Metformin.

Purpose: Dry eye syndrome (DES) is a global issue occurring due to tear deficiency or excessive tear evaporation. It is associated with a variety of symptoms causing ocular discomfort. The purpose of the study was to evaluate causative factors, treatment modalities, quality of life, and preservatives used in eye drops. Methods: This prospective, follow-up study was conducted in the ophthalmology outpatient department of a tertiary care teaching hospital. Patients older than 18 years of age of either sex diagnosed with DES and willing to give written informed consent were included. The patients were subjected to the Ocular surface disease index Questionnaire (OSDI Questionnaire) twice; at the time of the first visit and at 15 days follow-up. Results: A male preponderance was observed with a 1.86:1 male-to-female ratio. The mean age of the study population was 29.15 ± 10.07 years. The most common presenting complaints were symptoms related to dryness of the eyes followed by refractive error. Exposure to TV/computer screen for more than 6 hours is the most common causative factor. There was a statistically significant improvement in overall quality of life (QoL) in patients of DES on treatment. However, no significant difference was seen in the improvement of quality of life in comparison with different preservatives used in prescribed eye drops for the treatment of DES. Conclusion: DES can adversely affect the quality of life of patients. Prompt treatment of this condition can significantly improve the patient's QoL. Physicians should be encouraged to perform quality of life evaluations for patients with DES to guide them in treatment with more individual-specific treatment options.

Walking in high-heel shoes (HHS) decreases the push-off power and little research has examined the specific muscle groups that compensate for it. The purpose was to examine the effects of walking in HHS compared to barefoot on lower extremity net joint work and power. Fourteen young women walked in HHS and barefoot at a fixed speed of 1.3 m·s −1 . Marker position and ground reaction force data were synchronously measured at 100 and 1000 Hz, respectively. Peak power and joint work variables were computed over the power phases of the gait cycle using an inverse dynamic approach. When walking in HHS was compared to barefoot, participants exerted a diminished push-off characterized by lesser peak power and lesser work by the ankle plantar flexors in late stance (A2 phase; p < 0.001). To compensate for the reduced ankle plantar flexor power, greater peak power was generated and work was performed in early stance by hip extensors (H1 phase; p ≤ 0.001), in mid-stance by knee extensors (K2 phase; p < 0.001) and in late stance and early swing phase by hip flexor muscles (H3 phase; p ≤ 0.001). Walking in HHS induces biomechanical plasticity and causes distal-to-proximal redistribution of net joint power and work during walking.