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Purpose: Scalp cooling therapy (SCT) improves chemotherapy-induced alopecia (CIA), but there are few published data about its efficacy in an Asian-predominant population. We report our tertiary institution experience of SCT in patients with breast or gynaecological cancers undergoing chemotherapy., Methods: The Paxman scalp cooling system was employed for eligible women with breast or gynaecological cancers receiving anthracycline or taxane-based chemotherapy. Only patients with Grade (G) 0-1 alopecia by common terminology criteria for adverse events (CTCAE) version 4.0 were eligible initially, but patients with G2 alopecia were later included in the study. SCT was performed at each chemotherapy cycle, commencing 30 min prior to and continuing up to 90 min after completion of the drug infusion. Patients were assessed at the start and end of each session for hair preservation (defined as G0-2 alopecia) and comfort level of SCT (rated on a 5-point visual scale). The primary end point was success of hair preservation or hair regrowth after completion of all cycles of chemotherapy., Results: Eighty-three patients were enrolled over a period of 18 months from December 2017 to October 2019, with a total of 510 scalp cooling cycles performed. 94.0% (n = 78) of patients reported a comfort score of 3 and above, indicating that the procedure was comfortable, upon a 5-point visual scale. Patients receiving weekly paclitaxel had highest success in hair preservation at 76.7% (23/30 patients), with a lower rate of hair preservation observed for the 3 weekly paclitaxel regimen (50%, 2/4 patients). In contrast, only 1 patient (5.3%, 1/19 patients) who underwent chemotherapy with anthracycline and cyclophosphamide achieved hair preservation., Conclusion: SCT is well tolerated in an Asian-predominant population. Among women with breast or gynaecological cancers receiving taxane and/or anthracycline based chemotherapy, those who underwent SCT were about 50% more likely to achieve hair preservation or hair regrowth, as compared to historical controls., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Lessons Learned: Despite U.S. Food and Drug Administration approval to reduce alopecia, data on efficacy of scalp cooling in Black patients with cancer are limited by lack of minority representation in prior clinical trials. Scalp cooling devices may have less efficacy in Black patients; additional studies are required to explore the possible causes for this, including hair texture and cap design., Background: The Paxman scalp cooling (SC) device is U.S. Food and Drug Administration (FDA)-approved for prevention of chemotherapy-induced alopecia. Studies report 50%-80% success rates and high patient satisfaction, yet there have been no studies of SC in Black patients. We conducted a phase II feasibility study of Paxman SC with a planned enrollment of 30 Black patients receiving chemotherapy for stage I-III breast cancer., Methods: Black patients who planned to receive at least four cycles of chemotherapy with non-anthracycline (NAC) or anthracycline (AC) regimens were eligible. Alopecia was assessed by trained oncology providers using the modified Dean scale (MDS) prior to each chemotherapy session. Distress related to alopecia was measured by the Chemotherapy Alopecia Distress Scale (CADS)., Results: Fifteen patients enrolled in the intervention before the study was closed early because of lack of efficacy. Median MDS and CADS increased after SC, suggesting increased hair loss (p < .001) and alopecia distress (p = .04). Only one participant was successful in preventing significant hair loss; the majority stopped SC before chemotherapy completion because of grade 3 alopecia (>50% hair loss)., Conclusion: SC may not be efficacious in preventing alopecia in Black women. Differences in hair thickness, hair volume, and limitations of cooling cap design are possible contributing factors., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side-effect of taxane-based chemotherapy, causing progressive and often irreversible pain/sensitivity in the hands and feet. Prevention/treatments for CIPN are not well-developed and urgently needed. Limb cryocompression during chemotherapy has demonstrated promising early data of preventing/reducing CIPN severity. Currently there are no medical devices available that are dedicated to the specific requirements of CIPN prevention. As part of our ongoing development of a dedicated CIPN-prevention limb cryocompression system, this study documents the design & development of the wearable arm wrap, a central component of the system, from initial concept to a trial-ready prototype. A collaborative and multidisciplinary approach was adopted to address the complex and high-risk nature of this SME (Small Medium Enterprise)-centered medical device design & development process. The complementary collaboration unites multidisciplinary expertise spanning the scope of the project. Alongside the clinical, academic, and design & development expertise, the integration of commercial expertise is imperative to promote the market viability, and ultimate success, of the development. As the global leading experts in scalp cooling specializing in the prevention of chemotherapy-induced alopecia, UK-based SME Paxman Coolers Ltd is optimally positioned to support the commercial and regulatory dimensions. Development and adoption of a novel mixed-methodology (HudPAX) facilitated the integration of evidence-based and user-centered techniques to optimize the design & development approach and ensure integration of all critical design inputs. Alpha prototypes were designed through evidence-based approaches, with data from existing clinical trials utilized to determine the preliminary design inputs, alongside 3D ergonomic data. Investigations utilized computer-aided design, rapid prototyping, additive manufacturing, sketch modeling, and fast ideation. User-based approaches facilitated stakeholder-feedback through expert focus groups, informing further design & development and projecting the design into the next stage, Beta prototyping, for use in large-scale efficacy trials and upscaling manufacturing. This paper demonstrates a novel mixed-methods approach, which promotes cross-sector multidisciplinary collaboration, to address the complex multi-layered challenges posed by an early-stage medical device design & development process., Competing Interests: JB and PB are employed by Paxman Coolers Ltd. RP partially owns Paxman Coolers Ltd. EU, RS, and AB have received research or travel funding from Paxman Coolers Ltd. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was supported by Paxman Coolers Ltd., UK. The funder was involved in the commercial design decisions as this project is a commercial product design and development (not medical study), but the academic and research team independently made decisions for data collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication., (Copyright © 2020 Binder, Unver, Clayton, Burke, Paxman, Sundar and Bandla.)

Pharmacologic arm-selective unfolded protein response (UPR) signaling pathway activation is emerging as a promising strategy to ameliorate imbalances in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. The small molecule N- (2-hydroxy-5-methylphenyl)-3-phenylpropanamide ( 147 ) was previously identified (Plate et al., 2016) to preferentially activate the ATF6 arm of the UPR, promoting protective remodeling of the ER proteostasis network. Here we show that 147 -dependent ATF6 activation requires metabolic oxidation to form an electrophile that preferentially reacts with ER proteins. Proteins covalently modified by 147 include protein disulfide isomerases (PDIs), known to regulate ATF6 activation. Genetic depletion of PDIs perturbs 147 -dependent induction of the ATF6-target gene, BiP , implicating covalent modifications of PDIs in the preferential activation of ATF6 afforded by treatment with 147 . Thus, 147 is a pro-drug that preferentially activates ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity., Competing Interests: RP has submitted a patent application (WO2017117430A1) for the use of 147 and other compounds as ER proteostasis network regulators to treat protein misfolding diseases. LP Lars Plate: has submitted a patent application (WO2017117430A1) for the use of 147 and other compounds as ER proteostasis network regulators to treat protein misfolding diseases. EB, CG No competing interests declared, EP Evan T Powers: has submitted a patent application (WO2017117430A1) for the use of 147 and other compounds as ER proteostasis network regulators to treat protein misfolding diseases. RW R Luke Wiseman: has submitted a patent application (WO2017117430A1) for the use of 147 and other compounds as ER proteostasis network regulators to treat protein misfolding diseases. JK is a co-founder and member of the Scientific Advisory Board of Proteostasis Therapeutics Inc., who is independently pursing ATF6 activators; however, he is unaware of the structures of their activators, which were discovered by a totally different screening approach. Has submitted a patent application (WO2017117430A1) for the use of 147 and other compounds as ER proteostasis network regulators to treat protein misfolding diseases., (© 2018, Paxman et al.)

ATF6 encodes a transcription factor that is anchored in the endoplasmic reticulum (ER) and activated during the unfolded protein response (UPR) to protect cells from ER stress. Deletion of the isoform activating transcription factor 6α (ATF6α) and its paralog ATF6β results in embryonic lethality and notochord dysgenesis in nonhuman vertebrates, and loss-of-function mutations in ATF6α are associated with malformed neuroretina and congenital vision loss in humans. These phenotypes implicate an essential role for ATF6 during vertebrate development. We investigated this hypothesis using human stem cells undergoing differentiation into multipotent germ layers, nascent tissues, and organs. We artificially activated ATF6 in stem cells with a small-molecule ATF6 agonist and, conversely, inhibited ATF6 using induced pluripotent stem cells from patients with ATF6 mutations. We found that ATF6 suppressed pluripotency, enhanced differentiation, and unexpectedly directed mesodermal cell fate. Our findings reveal a role for ATF6 during differentiation and identify a new strategy to generate mesodermal tissues through the modulation of the ATF6 arm of the UPR., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Importance: Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial., Objectives: To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects., Design, Setting, and Participants: Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized., Interventions: Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device., Main Outcomes and Measures: The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale., Results: At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events., Conclusions and Relevance: Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects., Trial Registration: clinicaltrials.gov Identifier: NCT01986140.

PEGylation of protein side chains has been used for more than 30 years to enhance the pharmacokinetic properties of protein drugs. However, there are no structure- or sequence-based guidelines for selecting sites that provide optimal PEG-based pharmacokinetic enhancement with minimal losses to biological activity. We hypothesize that globally optimal PEGylation sites are characterized by the ability of the PEG oligomer to increase protein conformational stability; however, the current understanding of how PEG influences the conformational stability of proteins is incomplete. Here we use the WW domain of the human protein Pin 1 (WW) as a model system to probe the impact of PEG on protein conformational stability. Using a combination of experimental and theoretical approaches, we develop a structure-based method for predicting which sites within WW are most likely to experience PEG-based stabilization, and we show that this method correctly predicts the location of a stabilizing PEGylation site within the chicken Src SH3 domain. PEG-based stabilization in WW is associated with enhanced resistance to proteolysis, is entropic in origin, and likely involves disruption by PEG of the network of hydrogen-bound solvent molecules that surround the protein. Our results highlight the possibility of using modern site-specific PEGylation techniques to install PEG oligomers at predetermined locations where PEG will provide optimal increases in conformational and proteolytic stability.

PEGylation, or addition of poly(ethylene glycol) chains to proteins, is widely used to improve delivery in pharmaceutical applications. Recent studies suggest that stabilization of a protein by PEG, and hence its proteolytic degradability, is sequence-dependent and requires only short PEG chains. Here we connect stabilization by short PEG chains directly to the structural dynamics of the protein and PEG chain. We measured the stability of human Pin1 WW domain with PEG-4 at asparagine 19 for a full mutant cycle at two positions thought to influence PEG-protein interaction: Ser16Ala and Tyr23Phe. We then performed explicit solvent molecular dynamics simulations on all PEGylated and PEG-free mutants. The mutant cycle yields a nonadditive stabilization effect where the pseudo-wild type and double mutant are more stabilized relative to unPEGylated proteins than are the two single mutants. The simulation reveals why: the double mutant suffers loss of β-sheet structure, which PEGylation restores even though the PEG extends as a coil into the solvent. In contrast, in one of the single mutants, PEG preferentially interacts with the protein surface while disrupting the interactions of its asparagine host with a nearby methionine side chain. Thus, PEG attachment can stabilize a protein differentially depending on the local sequence, and either by interacting with the surface or by extending into the solvent. A simulation with PEG-45 attached to asparagine 19 shows that PEG even can do both in the same context.

Recently the optical transmission matrix (TM) has been shown to be useful in controlling the propagation of light in highly scattering media. In this paper, we present the vector transmission matrix (VTM) which, unlike the TM, captures both the intensity and polarization transmission property of the scattering medium. We present an experimental technique for measuring the absolute values of the VTM elements which is in contrast to existing techniques whereby the TM elements are measured to within a scaling factor. The usefulness of the VTM is illustrated by showing that it can be used to both predict and control the magnitude of the complex polarization ratio of the light focused through the scattering medium. To the best of our knowledge, this is the first study to show the possibility of controlling the polarization of the light transmitted through highly scattering media.

Micromechanic resonators provide a small-volume and potentially high-throughput method to determine rheological properties of fluids. Here we explore the accuracy in measuring mass density and viscosity of ethanol-water and glycerol-water model solutions, using a simple and easily implemented model to deduce the hydrodynamic effects on resonating cantilevers of various length-to-width aspect ratios. We next show that these measurements can be extended to determine the alcohol percentage of both model solutions and commercial beverages such as beer, wine and liquor. This demonstrates how micromechanical resonators can be used for quality control of every-day drinks.

A nine-aperture, wide-field Fizeau imaging telescope has been built at the Lockheed-Martin Advanced Technology Center. The telescope consists of nine, 125 mm diameter collector telescopes coherently phased and combined to form a diffraction-limited image with a resolution that is consistent with the 610 mm diameter of the telescope. The phased field of view of the array is 1 murad. The measured rms wavefront error is 0.08 waves rms at 635 nm. The telescope is actively controlled to correct for tilt and phasing errors. The control sensing technique is the method known as phase diversity, which extracts wavefront information from a pair of focused and defocused images. The optical design of the telescope and typical performance results are described.

Space-variant blur is encountered when objects extend beyond the isoplanatic patch associated with the intervening atmospheric turbulence. The method of phase diversity, used to estimate jointly the object and the aberrations, is generalized to accommodate turbulence-induced space-variant blur. This generalization utilizes a parametric model for the blur function that is constructed with multiple phase screens. Simulation results are presented that demonstrate the recovery of near-diffraction-limited imagery from phase-diversity imagery that has been degraded with rather severe anisoplanatism.

Two algorithms have been developed for reconstructing objects from their coded images and a priori knowledge of the object class. Reconstructions from both algorithms are presented, but the results appear to be largely independent of the algorithm used. One of the algorithms, a Monte Carlo approach, is used to investigate the quality of the reconstruction of two- and three-dimensional objects from simulated coded-image data with respect to viewing geometry and multiplexing (mixing) of the data. The cases examined include reconstructions from data with and without signal-dependent photon noise. It is found that reconstructing from multiplexed data is not so serious a problem as reconstructing from data obtained with a limited viewing angle. Also, when photon noise is included in the data, reconstructions obtained from multiplexed data are better than those obtained from unmultiplexed data because of the higher photon count made available by multiplexing. It appears that the fidelity of a reconstruction depends much more strongly on the design of the data-taking system (the coded apertures) than on the reconstruction algorithm.

A new Monte Carlo reconstruction procedure is presented for retrieval of objects from their coded images. The reconstruction process is modeled as an optimization problem whose cost function is related to how well the coded image constraints are satisfied. Reduction of the cost function is achieved by an annealing process analogous to the cooling of a melt to produce an ordered crystal. The method is demonstrated by reconstructing two two-dimensional objects from their one-dimensional coded images.

A strategy is given for the design of coded apertures with respect to a given class of objects that are to be imaged. Previous knowledge of the first- and second-order statistics for the object class is assumed. The object class is characterized by its Karhunen-Loève eigenvectors and eigenvalues, whereas the imaging system is characterized by its singular-value decomposition. We introduce the concept of alignment in which the aperture parameters are adjusted until the system is tuned to measure the given object class well. A mean-square-error figure of merit that indicates degree of alignment is given, and alignment is performed by standard optimization techniques. We illustrate this technique with a simple proof-of-principle experiment. These concepts are general and may be applied to any linear imaging system.