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The immune system plays an important role in the evolution of malignancy and has become an important target for novel antineoplastic agents. This review article focuses on key features of tumor immunology, including the role of immunotherapy in general and as it pertains to head and neck squamous cell carcinoma. Side effects, resistance mechanisms, and therapeutic monitoring strategies pertaining to immunotherapy are discussed. [ABSTRACT FROM AUTHOR]

The methionine sulfoxide reductase (Msr) system (comprised of MsrA and MsrB) is responsible for reducing methionine sulfoxide (MetO) to methionine. One major form of MsrB is a selenoprotein. Following prolonged selenium deficient diet (SD), through F2 generation, the MsrA - / -mice exhibited higher protein–MetO and carbonyl levels relative to their wild-type (WT) control in most organs. More specifically, the SD diet caused alteration in the expression and/or activities of certain antioxidants as follows: lowering the specific activity of MsrB in the MsrA - / -cerebellum in comparison to WT mice; lowering the activities of glutathione peroxidase (Gpx) and thioredoxin reductase (Trr) especially in brains of MsrA - / -mice; elevation of the cellular levels of selenoprotein P (SelP) in most tissues of the MsrA - / -relative to WT. Unexpectedly, the expression and activity of glucose-6-phosphate dehydrogenase (G6PD) were mainly elevated in lungs and hearts of MsrA - / -mice. Moreover, the body weight of the MsrA - / -mice lagged behind the WT mice body weight up to 120 days of the SD diet. In summary, it is suggested that the lack of the MsrA gene in conjunction with prolonged SD diet causes decreased antioxidant capability and enhanced protein oxidation. [ABSTRACT FROM AUTHOR]

W. M. Williams, E. R. Stadtman and J. Moskovitz (2004) Neuropathology and Applied Neurobiology, doi: 10.1111/j.1365-2990.2004.00523.x Ageing and exposure to oxidative stress in vivo differentially affect cellular levels of PrPc in mouse cerebral microvessels and brain parenchyma The biological function of cellular prion protein PrPc has not been established, despite in vitro studies suggesting antioxidant activity or link to signal transduction pathways. In this study, mice were exposed to hyperoxia to establish whether oxidative stress affected prion expression in vivo. C57Bl/6J mice aged 6, 18, and 24 months, maintained under normoxic conditions, exhibited age-related increases in PrPc in both cerebral microvessels and in microvessel-depleted brain homogenate. We demonstrate that PrPc is differentially affected by exposure to hyperoxia in vivo for 1 (24 h) or 2 (48 h) days, or for 1 day hyperoxia, followed by 1 day normoxia. Brain parenchymal cells from 6-month-old mice exposed to 1 day hyperoxia showed elevation of a glycosylated ∼36 kDa form, whereas in 24-month-old mice cellular prion level was substantially reduced. Extending hyperoxia from 1 to 2 days resulted in significantly reduced PrPc level, regardless of age. Parenchymal PrPc is substantially elevated in 6-month-old mice, but declines in 18- and 24-month-old animals following 1 day hyperoxia. By contrast, PrPc content in cerebral microvessels from 6-month-old mice declined after a 2 day exposure to hyperoxia, while microvessels from 24-month-old brains showed elevated prion levels 24 h after hyperoxia. Moreover, unglycosylated 25–30 kDa PrPc, and a previously undescribed 50–64 kDa band containing at least some glycosylated protein, predominated in microvessels with lesser content of the glycosylated ∼36 kDa form. Cellular content of these unglycosylated forms was correlated with age, while the response to hyperoxia was evident in both unglycosylated and glycosylated forms of the protein following 1 and 2 day exposures. The observed elevation of the 25–30 and 50–64 kDa bands of microvessel PrPc is not sustainable following 1 day hyperoxia, but returns to near normoxic levels within 24 h after hyperoxia. We also show in a knockout mouse for methionine sulfoxide reductase (MsrA), the enzyme responsible for reducing methionine sulfoxide back to methionine, and a regulator of cellular antioxidant defence, that following hyperoxia brain PrPc in the null mutant is elevated relative to PrPc content in the parent strain. Our results show up-regulated PrPc expression or reduced turnover in response to age-related, and hyperoxia-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Cites findings of a study which reveals that plant stress hormones are capable of suppressing apoptosis in various transformed human cells including leukemia, melanoma, prostate and breast cell cancer. Revelation that methyl jasmonate (MJ) was determined to be the most potent agent in suppressing apoptosis; Information that MJ killed Molt-4 human lymphoblastic leukemia cells in efficient manner; Observation that MJ did not affect normal human peripheral blood lymphocytes; Details of methodology adopted for the study to assess the effectiveness of MJ against lymphoblastic leukemia cells.

Presents a corrected reprint of an article published in the periodical "Leukemia".

Clusterin is a secreted glycoprotein that participates in multiple physiological processes through its chaperon function. In Alzheimer's disease, the brain functions under an increased oxidative stress condition that causes an elevation of protein oxidation, resulting in enhanced pathology. Accordingly, it is important to determine the type of human brain cells that are mostly prone to methionine oxidation in Alzheimer's disease and specifically monitoring the methionine-oxidation levels of clusterin in human and mice brains and its effect on clusterin's function. We analyzed the level of methionine sulfoxide (MetO)-clusterin in these brains, using a combination of immunoprecipitation and Western-blott analyses. Also, we determine the effect of methionine oxidation on clusterin ability to bind beta-amyloid, in vitro, using calorimetric assay. Our results show that human neurons and astrocytes of Alzheimer's disease brains are mostly affected by methionine oxidation. Moreover, MetO-clusterin levels are elevated in postmortem Alzheimer's disease human and mouse brains in comparison to controls. Finally, oxidation of methionine residues of purified clusterin reduced its binding efficiency to beta-amyloid. In conclusion, we suggest that methionine oxidation of brain-clusterin is enhanced in Alzheimer's disease and that this oxidation compromises its chaperon function, leading to exacerbation of beta-amyloid's toxicity in Alzheimer's disease., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Obesity remains a high-level risk factor for various cancers. Yet, some research has shown that higher BMIs may improve survival outcomes, particularly for head and neck squamous cell carcinoma (HNSCC). While this is a clear deviation from the norm, it raises the question of what other effects obesity may have on head and neck cancer patients, including surgical outcomes. Choosing the most appropriate flap for patients can be difficult for even experienced surgeons. Head and neck reconstructive surgeries are no exception to this rule and can be especially challenging. To produce the most favorable outcomes, a physician must be able to combine all flap attributes including donor and recipient site location, flap thickness, as well as each patient's individual risk factors such as prior radiation. Purpose: The purpose of this study was to compare the outcomes of vertical rectus femoris myocutaneous (VRAM) and anterolateral thigh (ALT) flaps in overweight and obese individuals with varying head and neck cancers leaving large-sized defects to the outcomes in normal and underweight patients. Methods: A retrospective chart review was conducted of VRAM and ALT flaps performed over a period of 12 months at our university hospital for large head and neck reconstruction. Results: Of the 17 ALT patients, 80% (4/5) of the underweight patients, 57% (4/7) of the normal weight patients, 50% (1/2) of the overweight patients, and 33% (1/3) of the obese patients experienced complications. Of the 15 VRAM patients, 40% (2/5) of the underweight patients, 83% (5/6) of the overweight patients, and 50% (1/2) of the obese patients experienced complications. Conclusions: In our small sample size, a smaller percentage of obese patients with head and neck cancer who underwent flap reconstruction surgery had complications when undergoing ALT flaps than VRAM flaps, which contrasts with the normal and underweight patients, who had less complications with VRAM flaps than ALT flaps., Competing Interests: The authors have no conflicts of interest to declare.

Background: Reducing unnecessary routine laboratory testing is a Choosing Wisely® recommendation, and new areas of overuse were noted during the COVID-19 pandemic., Objective: To reduce unnecessary repetitive routine laboratory testing for patients with COVID-19 during the pandemic across a large safety net health system., Designs, Settings and Participants: This quality improvement initiative was initiated by the System High-Value Care Council at New York City Health + Hospitals (H + H), the largest public healthcare system in the United States consisting of 11 acute care hospitals., Intervention: four overused laboratory tests in noncritically ill hospitalized patients with COVID-19 were identified: C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and procalcitonin. A two-pronged electronic health record intervention was implemented consisting of (1) nonintrusive, informational nudge statements placed on selected order sets, and (2) a forcing function of one consecutive day limit on ordering., Main Outcome and Measures: The average of excess tests per encounter days (ETPED) for each of four target laboratory testing only in patients with COVID-19., Objective: Interdisciplinary System High-Value Care Council identified four overused laboratory tests (inflammatory markers) in noncritically ill hospitalized patients with COVID-19: C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH), and procalcitonin. Within an 11-hospital safety net health system, a two-pronged electronic health record intervention was implemented consisting of (1) nonintrusive, informational nudge statements placed on selected order sets, and (2) a forcing function of one consecutive day limit on ordering. The preintervention period (March 16, 2020 to January 24, 2021) was compared to the postintervention period (January 25, 2021 to March 22, 2022)., Results: Time series linear regression showed decreases in CRP (-17.9%, p < .05), ferritin (-37.6%, p < .001), and LDH (-30.1%, p < .001). Slope differences were significant (CRP, ferritin, and LDH p < 0.001; procalcitonin p < 0.05). Decreases were observed across weekly averages: CRP (-19%, p < .01), ferritin (-37.9%, p < .001), LDH (-28.7%, p < .001), and procalcitonin (-18.4%, p < .05)., Conclusion: This intervention was associated with reduced routine inflammatory marker testing in non-intensive care unit COVID-19 hospitalized patients across 11 hospitals. Variation was high among individual hospitals., (© 2022 Society of Hospital Medicine.)

Mice with constitutive disruption of the Selenop gene have been key to delineate the importance of selenoproteins in neurobiology. However, the phenotype of this mouse model is exquisitely dependent on selenium supply and timing of selenium supplementation. Combining biochemical, histological, and behavioral methods, we tested the hypothesis that parvalbumin-expressing interneurons in the primary somatosensory cortex and hippocampus depend on dietary selenium availability in Selenop -/- mice. Selenop-deficient mice kept on adequate selenium diet (0.15 mg/kg, i.e. the recommended dietary allowance, RDA) developed ataxia, tremor, and hyperexcitability between the age of 4-5 weeks. Video-electroencephalography demonstrated epileptic seizures in Selenop -/- mice fed the RDA diet, while Selenop ± heterozygous mice behaved normally. Both neurological phenotypes, hyperexcitability/seizures and ataxia/dystonia were successfully prevented by selenium supplementation from birth or transgenic expression of human SELENOP under a hepatocyte-specific promoter. Selenium supplementation with 10 μM selenite in the drinking water on top of the RDA diet increased the activity of glutathione peroxidase in the brains of Selenop -/- mice to control levels. The effects of selenium supplementation on the neurological phenotypes were dose- and time-dependent. Selenium supplementation after weaning was apparently too late to prevent ataxia/dystonia, while selenium withdrawal from rescued Selenop -/- mice eventually resulted in ataxia. We conclude that SELENOP expression is essential for preserving interneuron survival under limiting Se supply, while SELENOP appears dispensable under sufficiently high Se status., Competing Interests: Declaration of competing interest L.S. holds shares of selenOmed GmbH, a company involved in Se status assessment. All other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine (Met35) of beta-amyloid (A β ), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of A β and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age. Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced A β levels in both blood-plasma and brain; reduced A β burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions. These data collected in a preclinical AD model are likely translational, showing that active immunization could give a possibility of delaying or preventing AD onset. This study represents a first step toward the complex way of starting clinical trials in humans and conducting the further confirmations that are needed to go in this direction.

Purpose: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy., Patients and Methods: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives., Results: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N  =  12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08)., Conclusions: The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy., (©2022 American Association for Cancer Research.)

Background: Clinician champions are front-line clinicians who advocate for and influence practice change in their local context. The strategies they use when leading efforts to reduce the use of low-value care have not been well described. The purpose of this study is to identify and describe strategies used by six clinician champions who led a low-value care initiative in their clinical setting., Methods: Qualitative data collected during an overuse reduction initiative led by clinician champions were used to identify strategies, guided by the Expert Recommendations for Implementing Change compilation of strategies. Clinician champions were asked to rank the importance of these activities and indicate which one of the six most important activities they would be willing to discuss in an interview. A 30-min semi-structured interview was conducted with each clinician about the activity they selected and thematically analyzed., Results: Twelve Expert Recommendations for Implementing Change strategies were identified. The top six strategies discussed during interviews were: build a coalition, conduct a local needs assessment, develop a formal implementation blueprint, conduct educational meetings, use facilitation, and develop clinical reminders. Common themes that emerged across all interviews were the use of data to engage clinicians in conversations, including the patient's perspective in designing the interventions, and investing the time upfront to plan and launch the initiative because of the inherent challenges of relinquishing a service., Conclusions: Clinician champions identified multiple strategies as important when de-implementing a low-value service. Many were used to engage in conversations with stakeholders, including leadership, providers, and patients, to increase buy-in and support, challenge beliefs, promote behavior change, and gather insights about next steps in their effort. Future work is needed to better understand how prepare clinicians for this role and to understand the mechanisms through which these strategies might be effective., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Despite the success of immune checkpoint blockade therapy, few strategies sufficiently overcome immunosuppression within the tumor microenvironment (TME). Targeting regulatory T cells (T regs ) is challenging, because perturbing intratumoral T reg function must be specific enough to avoid systemic inflammatory side effects. Thus, no T reg -targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral T reg function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1 + T regs and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral T regs across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1 + T reg prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1 + T regs have broad activation programs and elevated suppressive function. Unlike mouse T regs , we demonstrate that NRP1 identifies a transient activation state of human T regs driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1 + T regs in patient PBL correlates with the intratumoral abundance of NRP1 + T regs and may indicate higher disease burden. These findings support further clinical evaluation of NRP1 as a suitable therapeutic target to enhance antitumor immunity by inhibiting T reg function in the TME.

Methionine oxidation and reduction is a common phenomenon occurring in biological systems under both physiological and oxidative-stress conditions. The levels of methionine sulfoxide (MetO) are dependent on the redox status in the cell or organ, and they are usually elevated under oxidative-stress conditions, aging, inflammation, and oxidative-stress related diseases. MetO modification of proteins may alter their function or cause the accumulation of toxic proteins in the cell/organ. Accordingly, the regulation of the level of MetO is mediated through the ubiquitous and evolutionary conserved methionine sulfoxide reductase (Msr) system and its associated redox molecules. Recent published research has provided new evidence for the involvement of free MetO or protein-bound MetO of specific proteins in several signal transduction pathways that are important for cellular function. In the current review, we will focus on the role of MetO in specific signal transduction pathways of various organisms, with relation to their physiological contexts, and discuss the contribution of the Msr system to the regulation of the observed MetO effect.

Over the past century, society has achieved great gains in medicine, public health, and health-care infrastructure, particularly in the areas of vaccines, antibiotics, sanitation, intensive care and medical technology. Still, despite these developments, infectious diseases are emerging at unprecedented rates around the globe. Large urban centers are particularly vulnerable to communicable disease events, and must have well-prepared response systems, including on the front-line level. In November 2018, the United States' largest municipal health-care delivery system, New York City Health + Hospitals, hosted a half-day executive-level pandemic response workshop, which sought to illustrate the complexity of preparing for, responding to, and recovering from modern-day infectious diseases impacting urban environments. Attendees were subjected to a condensed, plausible, pandemic influenza scenario and asked to simulate the high-level strategic decisions made by leaders by internal (eg, Chief Medical Officer, Chief Nursing Officer, and Legal Affairs) and external (eg, city, state, and federal public health and emergency management entities) partners across an integrated system of acute, postacute, and ambulatory sites, challenging players to question their assumptions about managing the consequences of a highly pathogenic pandemic.