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In cancer and chronic viral infections, T cells are exposed to persistent antigen stimulation. This results in expression of multiple inhibitory receptors also called “immune checkpoints” by T cells. Although these inhibitory receptors under normal conditions maintain self-­tolerance and prevent immunopathology, their sustained expression deteriorates T cell function: a phenomenon called exhaustion. Recent advances in cancer immunotherapy involve blockade of cytotoxic T lymphocyte antigen­4 and programmed cell death 1 in order to reverse T cell exhaustion and reinvigorate immunity, which has translated to dramatic clinical remission in many cases of metastatic melanoma and lung cancer. With the paucity of therapeutic vaccines against chronic infections such as HIV, HPV, hepatitis B, and hepatitis C, such adjunct checkpoint blockade strategies are required including the blockade of other inhibitory receptors such as T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-­based inhibitory motif domains, T cell Ig and mucin­-domain containing­3, lymphocyte activation gene 3, and V­-domain Ig­-containing suppressor of T cell activation. The nature of different chronic viral infections and cancers is likely to influence the level, composition, and pattern of inhibitory receptors expressed by responding T cells. This will have implications for checkpoint antibody blockade strategies employed for treating tumors and chronic viral infections. Here, we review recent advances that provide a clearer insight into the role of coinhibitory receptor expression in T cell exhaustion and reveal novel antibody­blockade therapeutic targets for chronic viral infections and cancer. Understanding the mechanism of T cell exhaustion in response to chronic virus infections and cancer as well as the nature of restored T cell responses will contribute to further improvement of immune checkpoint blockade strategies. [ABSTRACT FROM AUTHOR]

Many pharmacological and toxicological actions of drugs in children cannot be fully predicted from adult clinical experience or from standard non-clinical toxicology studies. Numerous drugs have direct or indirect pharmacological effects on the heart and are prescribed for children of all ages. Toxicity or secondary effects may be immediate or delayed for years after drug exposure has ceased. Originally, the aim of this review was to compile information on the effect of specific drugs on the post-natal development of the cardiovascular system and to examine long-term follow-up of the use of cardio-active drugs in children. The limited database of published information caused the original question to evolve into an examination of the medical literature for three areas of information: (i) whether vulnerable developmental windows have been identified that reflect the substantial functional development that the cardiovascular system undergoes after birth; (ii) what is known about pharmacological perturbation of development; and (iii) what the likelihood is of drug exposure during childhood. We examined different scenarios for exposure including random, isolated exposure, conditions historically associated with adults, primary or secondary cardiac disease, psychiatric and neurological conditions, asthma, cancer and HIV. Except for random, isolated drug exposures, each category of possible exposure contained numerous drugs known to have either primary or secondary effects on the cardiovascular system or to influence factors associated with atherosclerosis. It is likely that a significant number of children will be prescribed drugs having either direct or indirect effects upon the immature cardiovascular system. A confounding factor is the simultaneous use of over-the-counter medications and herbal or nutraceutical preparations that a patient, parent or guardian does not mention to a prescribing physician. Metabolism is also important in assessing drug effects in children. Differences in body water : body fat ratio, age-related gastrointestinal absorption, distribution, excretion, renal function and drug metabolizing capabilities make it possible for children to have a different metabolite profile for a drug compared with adults. There is little examination of drug effects on the interdependent processes of cardiac maturation and less examination of metabolite effects. It is difficult to identify delayed toxicities in children as these adverse events may take years to manifest with many patients lost to follow-up. Clearly this is an area of study where intermediate endpoints and surrogate markers would be of great benefit. Pharmacogenomics may be useful in providing markers of increased risk or susceptibility. A perspective must be kept in balancing the possibility of a problem with the very real benefits that many children experience from the use of these pharmaceuticals. [ABSTRACT FROM AUTHOR]

We have previously reported the stability of europium oxalate compared to ammonium europium bis-salen and europium benzoate. We now extend the dicoarboxylic acid chain of the oxalate by introducing additional-CH2-groups in the dicarboxylate ligands by using malonate, succinate, glutarate and adipate. Additionally, we have examined the effect of alterations in the succinate dianion by introducing functional groups such as [C = C]in the case of the maleide and-OH group in the case of the malide. This study is an attempt to further characterize these compounds. Infrared spectra were used to characterize bridging and chelating dicarboxylates while Mössbauer spectroscopy measurements were used to gain better insight into the structure of heterocyclic “cages” containing two Eu3 + ions and two dianions. [ABSTRACT FROM AUTHOR]

The use of Mössbauer spectroscopy to investigate nanoparticle systems is fairly widespread. In this study, nanoparticles of a europium salen complex, NH4 Eu (salen)2, were prepared by the sol–gel method, and its properties investigated using infrared and Mössbauer spectroscopy. The size of the nanoparticles was measured using an atomic force microscope. The Debye temperature of the nanoparticles was determined from the Mössbauer spectrum and compared with the Debye temperature of the salen complex previously reported. The infrared spectral data support the Mössbauer spectroscopic results. [ABSTRACT FROM AUTHOR]

The needs of families to reconstruct their relationships in response to the DNA testing for Huntington disease of one or more of their asymptomatic members are presented. Data were collected from family interviews with 18 families, and from their responses on a post interview questionnaire. Findings are that families need to (a) address 'unfinished business' associated with the decision for testing; (b) bring family members, peripheral in the decision for testing, into the loop; (c) reorganize patterns of communication and roles altered by the testing and heal ruptures in family membership; and (d) revise family stories about illness to provide a meaning for HD and explain the test results in a way that leaves them with a sense of mastery. Findings suggest that families should be more involved in the initial decision for testing of a member and that protocols should be established to provide help for their ongoing adjustment. [ABSTRACT FROM AUTHOR]

Presents a review of US Food and Drug Administration regulatory concerns at each phase of drug development. New drugs based on modifications of available agents; Drugs acting through novel mechanisms to alter plasma lipoprotein levels and structure; Therapies whose presumed salutary actions in decreasing atherosclerotic disease risk are via nonlipid effects.

Background and Purpose: We conducted a multicentre real-world study to assess the outcomes of radical salvage re-irradiation for non-melanoma skin cancer (nMSC) recurrences following definitive or postoperative radiotherapy., Materials and Methods: Data on patients treated between 2006 and 2022 with re-irradiation for nMSCs were retrospectively collected from five high-volume brachytherapy centers. The primary endpoint was local control (LC). Secondary endpoints included overall survival, progression-free survival, and adverse events (AEs). The Kaplan-Meier estimator and Cox Proportional-Hazards Model were utilised in the analysis., Results: A total of 58 patients with a median age of 78.4 years with recurrences of previously irradiated nMSC in the head and neck region were included in the analysis. The majority had cutaneous basal cell carcinoma (BCC; 91.4%), and were irradiated with high-dose-rate brachytherapy (HDR-BT; 91.4%). The most common locations included the nasal region (36.2%) and external ear (18.9%). The 1-year LC was 73.1% and decreased to 41.7% at three years. The size of the re-irradiated lesion was the single independent prognostic factor in Cox analysis (per mm; HR 1.07; 95% CI 1.04-1.11; p < 0.001). Grade 3 or worse AEs were reported in 7 cases (12.1%)., Conclusion: Re-irradiation for nMSCs, predominantly administered with brachytherapy for radiorecurrent BCC, is associated with high recurrence rates, and the risk of failure significantly increases with the size of the treated lesion. Re-irradiation could be an option for selected elderly patients with small, localised, inoperable recurrences after RT to achieve local control or defer systemic treatment; however, prospective trials are necessary to confirm its safety and efficacy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The aim of this retrospective study was to assess the adverse effects and outcomes of salvage re-irradiation with stereotactic body radiotherapy (sSBRT) for local recurrence of prostate cancer (PCa) after definitive radiotherapy (RT). The study was focused on the adverse effects and prognostic factors for treatment toxicity, followed by an analysis of patterns of failure and survival. Patients treated with sSBRT between 2012 and 2020 at a tertiary institution were included. The exclusion criteria were a primary or salvage radical prostatectomy or a palliative sSBRT dose. Patients with oligorecurrence were eligible if all metastatic lesions were treated locally with curative intent. The Kaplan-Meier method was used to estimate time to grade ≥ 3 toxicity, local control (LC), freedom from distant metastases (FFDM), progression-free survival (PFS), biochemical control (BC) and overall survival (OS). The differences between groups (focal vs. whole-gland sSBRT) were compared using the log-rank test. The Cox proportional hazards model was used to assess prognostic factors for the listed endpoints. A total of 56 patients with a median age of 70.9 years and a median follow-up of 38.6 months were included in the analysis. The majority of them received local sSBRT only (45; 80.4%), while the rest were simultaneously treated for oligometastases (11; 19.6%). Overall, 18 (32.1%) patients experienced any grade ≥ 3 toxicity, including 1 (6.7%) patient who received focal sSBRT, and 17 (41.5%) patients treated with whole-gland sSBRT. The Planning Target Volume (per cc; HR 1.01; 95% CI 1-1.02; p = 0.025) and use of ADT (yes vs. no; HR 0.35; 95%CI 0.13-0.93; p = 0.035) were independent prognostic factors for the risk of grade ≥ 3 toxicity. The estimated rate of grade ≥ 3 adverse events was significantly higher (43.8% vs. 7.1% at 2 years; p = 0.006), and there was no improvement in the LC (92.9% vs. 85.3% at 2 years; p = 0.759) in patients treated with whole-gland sSBRT compared to focal sSBRT. The 2- and 5-year LC were 87.6% and 47.9%, respectively; the 2- and 5-year FFDM were 72.7% and 42.8%, respectively; and the 2- and 5-year PFS were 67.9% and 28.7%, respectively. The primary pattern of failure was distant metastasis. The sSBRT for local recurrence of PCa after definitive RT was associated with a high risk of severe grade ≥ 3 toxicity, which significantly increased with the volume and extent of re-irradiation.

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.

We who work with people with chronic and/or terminal illnesses are often confounded about what we ought to do and what we can do for those who suffer. This paper presents a case study of my work with Marion who began therapy after her presymptomatic testing for HD to address her depression and anxiety. The approach we took is a narrative one. The impact of illness on existing family stories is described followed by an examination of the premises of a narrative model. The case description demonstrates the collaborative nature of the therapy. Some thoughts on the role of the therapist in this model are offered.

Osteoporosis affects over 10 million Americans, including over 2 million men. Dentistry is in a position to work alongside medicine to assist the population in preventing and coping with this condition. This article provides an overview of osteoporosis, including its causes, assessment, prevention, and treatment. Various pharmacologic agents are reviewed, including bisphosphonates, selective estrogen receptor modulators, calcitonin, anabolic agents, and fluoride. The article also discusses the dentist's role in prevention, risk assessment, diagnosis, nutrition counseling, and evaluating the impact of the disease and its treatment on dental management and treatment planning. As dental implants become more in demand, the prognosis for and potential complications of implant therapy in patients with osteoporosis are a matter of intense interest.