► We examine a novel class of optimization problems that model restoring infrastructure systems. ► These new problems integrate network design and scheduling decisions. ► We utilize residual network ...optimality conditions in creating a dispatching rule. ► Our models and algorithms are tested on realistic case studies of infrastructure systems. ► The dispatching rule can be utilized in real-time restoration planning activities.
We consider the problem of restoring services provided by infrastructure systems after an extreme event disrupts them. This research proposes a novel integrated network design and scheduling problem that models these restoration efforts. In this problem, work groups must be allocated to build nodes and arcs into a network in order to maximize the cumulative weighted flow in the network over a horizon. We develop a novel heuristic dispatching rule that selects the next set of tasks to be processed by the work groups. We further propose families of valid inequalities for an integer programming formulation of the problem, one of which specifically links the network design and scheduling decisions. Our methods are tested on realistic data sets representing the infrastructure systems of New Hanover County, North Carolina in the United States and lower Manhattan in New York City. These results indicate that our methods can be used in both real-time restoration activities and long-term scenario planning activities. Our models are also applied to explore the effects on the restoration activities of aligning them with the goals of an emergency manager and to benchmark existing restoration procedures.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Sarcoidosis, a systemic inflammatory disease, poses challenges in understanding its etiology and variable clinical courses. Despite ongoing uncertainty about causative agents and genetic ...predisposition, granuloma formation remains its hallmark feature. To address this, we developed a validated in vitro human granuloma model using patient-derived peripheral blood mononuclear cells (PBMCs), offering a dynamic platform for studying early granuloma formation and sarcoidosis pathogenesis. However, a current limitation of this model is its dependence on freshly isolated PBMCs obtained from whole blood. While cryopreservation is a common method for long-term sample preservation, the biological effects of freezing and thawing PBMCs on granuloma formation remain unclear. This study aimed to assess the viability and functionality of cryopreserved sarcoidosis PBMCs within the granuloma model, revealing similar granulomatous responses to fresh cells and highlighting the potential of cryopreserved PBMCs as a valuable tool for studying sarcoidosis and related diseases.
•Cryopreserved PBMCs from sarcoidosis patients produce similar granulomas in model.•Cryopreserved PBMCs show largely consistent cytokine responses to fresh cells.•Study underscores compatibility of cryopreserved PBMCs in granulomatous disease models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Congenital melanocytic nevi are present at birth or develop within the first few months of life. Giant congenital melanocytic nevi are a rare variant and may involve the external genitalia with a ...confluent "bathing trunk" distribution. Rapid growth of proliferative nodules of melanocytic cells may cause disfigurement and anatomical distortion resulting in psychological distress and loss of functionality. We report the case of a neglected 17-year-old nonverbal male who received a resection of a Giant Congenital Melanocytic Nevi (GMN) engulfing the penis and scrotum with final resected dimensions of 36.0×20.0×8.0 cm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose of Review
Germline genetic variants contribute to a substantial proportion of cases of cancer in childhood. The purpose of this review is to describe two emerging pediatric cancer ...predisposition syndromes, including published surveillance protocols, as well as the psychological impacts related to childhood cancer predisposition.
Recent Findings
DICER1
syndrome is pleotropic, predisposing to a variety of tumors and likely phenotypically broader than currently realized. Rhabdoid tumor predisposition syndrome carries a risk for development of aggressive malignancies occurring in nearly any tissue.
Summary
New pediatric hereditary cancer syndromes are likely to be identified as genetic evaluation evolves. Advantages and disadvantages of genetic testing and surveillance protocols need to be discussed with patients and families in a team-based approach, with the input of a genetic counselor holding expertise in pediatric cancer predisposition. Finally, literature on psychosocial impacts of hereditary cancer syndromes in pediatric patients is sparse, necessitating further research.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This report documents a unique multicystic neoplasm of the liver in an 8-month-old boy with a heterozygous germline pathogenic DICER1 variant. This neoplasm, initially considered most likely a ...mesenchymal hamartoma based on imaging, demonstrated the characteristic histologic pattern of embryonal rhabdomyosarcoma residing in the subepithelial or cambium layer-like zone of the epithelial-lined cysts. Thus, although the differential diagnosis includes mesenchymal hamartoma, a young child with a multicystic mass lesion in the liver, lung, or kidney should both raise the possibility of a germline pathogenic DICER1 variant and also not be mistaken for one of the other hepatic neoplasms of childhood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Locally advanced cholangiocarcinoma has a poor prognosis, with long-term survival only for patients where complete surgical resection is achieved. Median overall survival with chemotherapy alone is ...less than 1 year. Novel strategies combining conventional chemotherapy and radiotherapy followed by targeted agents can lead to durable treatment responses and are applicable to cholangiocarcinoma management. Pediatric cholangiocarcinoma is exceedingly rare, with an estimate of 15–22 cases reported in the last 40 years. As such, no standard therapeutic regimen exists. We present a case of a 16-year-old previously healthy patient with unresectable cholangiocarcinoma whose tumor genetic sequencing revealed a novel, actionable neuregulin-1 (NRG1) gene translocation. The patient underwent standard systemic chemotherapy with gemcitabine and cisplatin followed by hypofractionated proton radiation therapy for local control. The patient then started an oral pan-ERBB (erythroblastic B receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4) family inhibitor as a maintenance medication, remaining with stable disease and excellent quality of life for over 2 years. This case highlights a novel NRG1 fusion in a rare clinical entity that provided an opportunity to utilize a multimodal therapeutic strategy in the pediatric setting.
Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human ...cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe ...the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
At least 5%–10% of malignancies occur secondary to an underlying cancer predisposition syndrome (CPS). For these families, cancer surveillance is recommended with the goal of identifying ...malignancy earlier, in a presumably more curable form. Surveillance protocols, including imaging studies, bloodwork, and procedures, can be complex and differ based on age, gender, and syndrome, which adversely affect adherence. Mobile health (mHealth) applications (apps) have been utilized in oncology and could help to facilitate adherence to cancer surveillance protocols.
Methods
Applying a user‐centered mobile app design approach, patients with a CPS and/or primary caregivers were interviewed to identify current methods for care management and barriers to compliance with recommended surveillance protocols. Broad themes from these interviews informed the design of the mobile app, HomeTown, which was subsequently evaluated by usability experts. The design was then converted into software code in phases, evaluated by patients and caregivers in an iterative fashion. User population growth and app usage data were assessed.
Results
Common themes identified included general distress surrounding surveillance protocol scheduling and results, difficulty remembering medical history, assembling a care team, and seeking resources for self‐education. These themes were translated into specific functional app features, including push reminders, syndrome‐specific surveillance recommendations, ability to annotate visits and results, storage of medical histories, and links to reliable educational resources.
Conclusions
Families with CPS demonstrate a desire for mHealth tools to facilitate adherence to cancer surveillance protocols, reduce related distress, relay medical information, and provide educational resources. HomeTown may be a useful tool for engaging this patient population.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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