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α-Sulfo alkyl ester surfactants: Impact of changing the alkyl chain length on the adsorption, mixing properties and response to electrolytes of the tetradecanoate

Wang Z, Li P, Ma K, Chen Y, Yan Z, Penfold J, et al.

J Colloid Interface Sci, 2021 Mar 15;586:876-890.
PMID: 33309145 DOI: 10.1016/j.jcis.2020.10.122

HYPOTHESIS: The α-sulfo alkyl ester, AES, surfactants are a class of anionic surfactants which have potential for improved sustainable performance in a range of applications, and an important feature is their enhanced tolerance to precipitation in the presence of multivalent counterions. It is proposed that their adsorption properties can be adjusted substantially by changing the length of the shorter alkyl chain, that of the alkanol group in the ester.
EXPERIMENTS: Surface tension and neutron reflectivity have been used to investigate the variation in the adsorption properties with the shorter alkyl chain length (methyl, ethyl and propyl), the impact of NaCl on the adsorption, the tendency to form surface multilayer structures in the presence of AlCl3, and the effects of mixing the methyl ester sulfonate with the ethyl and propyl ester sulfonates on the adsorption.
FINDINGS: The variations in the critical micelle concentration, CMC, the adsorption isotherms, the saturation adsorption values, and the impact of NaCl illustrate the subtle influence of varying the shorter alkyl chain length of the surfactant. The non-ideal mixing of pairs of AES surfactants with different alkanol group lengths of the ester show that the extent of the non-ideality changes as the difference in the alkanol length increases. The surface multilayer formation observed in the presence of AlCl3 varies in a complex manner with the length of the short chain and for mixtures of surfactants with different chains lengths.
Fulltext Global child and adolescent mental health perspectives: bringing change locally, while thinking globally

Kaku SM, Sibeoni J, Basheer S, Chang JP, Dahanayake DMA, Irarrazaval M, et al.

Child Adolesc Psychiatry Ment Health, 2022 Nov 07;16(1):82.
PMID: 36345001 DOI: 10.1186/s13034-022-00512-8

Child and adolescent mental health (CAMH) are a global priority. Different countries across the globe face unique challenges in CAMH services that are specific to them. However, there are multiple issues that are also similar across countries. These issues have been presented in this commentary from the lens of early career CAMH professionals who are alumni of the Donald J Cohen Fellowship program of the IACAPAP. We also present recommendations that can be implemented locally, namely, how promoting mental health and development of children and adolescents can result in better awareness and interventions, the need to improve quality of care and access to care, use of technology to advance research and practices in CAMH, and how investing in research can secure and support CAMH professionals and benefit children and adolescents across the globe. As we continue to navigate significant uncertainty due to dynamic circumstances globally, bolstering collaborations by "bringing change locally, while thinking globally" are invaluable to advancing global CAMH research, clinical service provision, and advancement of the field.
Adsorption and self-assembly in methyl ester sulfonate surfactants, their eutectic mixtures and the role of electrolyte

Xu H, Li P, Ma K, Welbourn RJL, Doutch J, Penfold J, et al.

J Colloid Interface Sci, 2018 Apr 15;516:456-465.
PMID: 29408135 DOI: 10.1016/j.jcis.2018.01.086

The α-methyl ester sulfonate, MES, anionic surfactants are a potentially important class of sustainable surfactants for a wide range of applications. The eutectic-like Kraft point minimum in the C16 and C18-MES mixtures is an important feature of that potential. Understanding their individual adsorption properties and the surface mixing of the eutectic mixtures are key to their wider exploitation. Neutron reflectivity has been used to investigate the adsorption at the air-water interface of the C16 and C18-MES surfactants and the eutectic mixture of C16 and C18-MES, in aqueous solution and in electrolyte. The micelle mixing of the eutectic mixture is investigated using small angle neutron scattering. The adsorption isotherms for C14 to C18-MES are found to scale with their critical micelle concentration value. The surface and micelle compositions of the C16 and C18-MES eutectic mixture differ from the eutectic composition; with compositions in the limit of high concentrations richer in C16-MES. The mixing properties are described by the pseudo phase approximation with a repulsive interaction between the two surfactants. The impact of the multivalent ions Al3+ on the adsorption at the air-water interface results in a transition from monolayer to multilayer adsorption.
Ramadan intermittent fasting and its association with health-related indices and exercise test performance in athletes and physically active individuals: an overview of systematic reviews

Trabelsi K, Ammar A, Boukhris O, Boujelbane MA, Clark C, Romdhani M, et al.

Br J Sports Med, 2024 Feb 07;58(3):136-143.
PMID: 37923379 DOI: 10.1136/bjsports-2023-106826

OBJECTIVE: To systematically review, summarise and appraise findings of published systematic reviews, with/without meta-analyses, examining associations between Ramadan fasting observance (RO), health-related indices and exercise test performances in athletes and physically active individuals.
DESIGN: Overview of systematic reviews with assessment of reviews' methodological quality.
DATA SOURCES: PubMed, Web of Science, Scopus, Cochrane Database of Systematic Reviews, SPORTDiscus, ProQuest, PsycINFO and SciELO.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Systematic reviews with/without meta-analyses examining associations of RO with health-related indices and exercise performances in athletes and physically active individuals.
RESULTS: Fourteen systematic reviews (seven with meta-analyses) of observational studies, with low-to-critically-low methodological quality, were included. Two reviews found associations between RO and decreased sleep duration in athletes and physically active individuals. One review suggested athletes may experience more pronounced reductions in sleep duration than physically active individuals. One review found associations between RO and impaired sleep quality in athletes and physically active individuals. RO was associated with decreased energy, carbohydrate and water intake in adult-aged athletes, but not adolescents. One review suggests RO was associated with athletes' increased feelings of fatigue and decreased vigour. No association was found between RO and athletes' lean mass or haematological indices. RO was unfavourably associated with changes in athletes' performance during high-intensity exercise testing.
CONCLUSION: Continuance of training during RO could be associated with athletes' mood state disturbances, decreased sleep duration and performance decline during high-intensity exercise testing, while preserving lean mass. However, careful interpretation is necessary due to the low-to-critically-low methodological quality of the included reviews.
Leptospirosis in "Eco-Challenge" athletes, Malaysian Borneo, 2000

Sejvar J, Bancroft E, Winthrop K, Bettinger J, Bajani M, Bragg S, et al.

Emerg Infect Dis, 2003 Jun;9(6):702-7.
PMID: 12781010

Adventure travel is becoming more popular, increasing the likelihood of contact with unusual pathogens. We investigated an outbreak of leptospirosis in "Eco-Challenge" multisport race athletes to determine illness etiology and implement public health measures. Of 304 athletes, we contacted 189 (62%) from the United States and 26 other countries. Eighty (42%) athletes met our case definition. Twenty-nine (36%) case-patients were hospitalized; none died. Logistic regression showed swimming in the Segama River (relative risk [RR]=2.0; 95% confidence interval [CI]=1.3 to 3.1) to be an independent risk factor. Twenty-six (68%) of 38 case-patients tested positive for leptospiral antibodies. Taking doxycycline before or during the race was protective (RR=0.4, 95% CI=0.2 to 1.2) for the 20 athletes who reported using it. Increased adventure travel may lead to more frequent exposure to leptospires, and preexposure chemoprophylaxis for leptospirosis (200 mg oral doxycycline/week) may decrease illness risk. Efforts are needed to inform adventure travel participants of unique infections such as leptospirosis.
Metabolic glycan labeling and chemoselective functionalization of native biomaterials

Ren X, Evangelista-Leite D, Wu T, Rajab TK, Moser PT, Kitano K, et al.

Biomaterials, 2018 11;182:127-134.
PMID: 30118980 DOI: 10.1016/j.biomaterials.2018.08.012

Decellularized native extracellular matrix (ECM) biomaterials are widely used in tissue engineering and have reached clinical application as biomesh implants. To enhance their regenerative properties and postimplantation performance, ECM biomaterials could be functionalized via immobilization of bioactive molecules. To facilitate ECM functionalization, we developed a metabolic glycan labeling approach using physiologic pathways to covalently incorporate click-reactive azide ligands into the native ECM of a wide variety of rodent tissues and organs in vivo, and into the ECM of isolated rodent and porcine lungs cultured ex vivo. The incorporated azides within the ECM were preserved after decellularization and served as chemoselective ligands for subsequent bioconjugation via click chemistry. As proof of principle, we generated alkyne-modified heparin, immobilized it onto azide-incorporated acellular lungs, and demonstrated its bioactivity by Antithrombin III immobilization and Factor Xa inhibition. The herein reported metabolic glycan labeling approach represents a novel platform technology for manufacturing click-reactive native ECM biomaterials, thereby enabling efficient and chemoselective functionalization of these materials to facilitate tissue regeneration and repair.
Fulltext Calpain Inhibition Restores Autophagy and Prevents Mitochondrial Fragmentation in a Human iPSC Model of Diabetic Endotheliopathy

Ong SB, Lee WH, Shao NY, Ismail NI, Katwadi K, Lim MM, et al.

Stem Cell Reports, 2019 03 05;12(3):597-610.
PMID: 30799273 DOI: 10.1016/j.stemcr.2019.01.017

The relationship between diabetes and endothelial dysfunction remains unclear, particularly the association with pathological activation of calpain, an intracellular cysteine protease. Here, we used human induced pluripotent stem cells-derived endothelial cells (iPSC-ECs) to investigate the effects of diabetes on vascular health. Our results indicate that iPSC-ECs exposed to hyperglycemia had impaired autophagy, increased mitochondria fragmentation, and was associated with increased calpain activity. In addition, hyperglycemic iPSC-ECs had increased susceptibility to cell death when subjected to a secondary insult-simulated ischemia-reperfusion injury (sIRI). Importantly, calpain inhibition restored autophagy and reduced mitochondrial fragmentation, concurrent with maintenance of ATP production, normalized reactive oxygen species levels and reduced susceptibility to sIRI. Using a human iPSC model of diabetic endotheliopathy, we demonstrated that restoration of autophagy and prevention of mitochondrial fragmentation via calpain inhibition improves vascular integrity. Our human iPSC-EC model thus represents a valuable platform to explore biological mechanisms and new treatments for diabetes-induced endothelial dysfunction.
Fulltext Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder

Maier R, Moser G, Chen GB, Ripke S, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Coryell W, et al.

Am J Hum Genet, 2015 Feb 05;96(2):283-94.
PMID: 25640677 DOI: 10.1016/j.ajhg.2014.12.006

Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk.
Fulltext Diagnostics to support elimination of lymphatic filariasis-Development of two target product profiles

Won KY, Gass K, Biamonte M, Dagne DA, Ducker C, Hanna C, et al.

PLoS Negl Trop Dis, 2021 11;15(11):e0009968.
PMID: 34780503 DOI: 10.1371/journal.pntd.0009968

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools.
Fulltext γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial

Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN, et al.

Lancet Oncol, 2023 Jul;24(7):811-822.
PMID: 37414012 DOI: 10.1016/S1470-2045(23)00246-2

BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma.
METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals.
FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached.
INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials.
FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.
Fulltext Pathway to global elimination of hepatitis B: HBV cure is just the first step

Howell J, Seaman C, Wallace J, Xiao Y, Scott N, Davies J, et al.

Hepatology, 2023 Sep 01;78(3):976-990.
PMID: 37125643 DOI: 10.1097/HEP.0000000000000430

Hepatitis B (HBV) is a major cause of global morbidity and mortality, and the leading cause of liver cancer worldwide. Significant advances have recently been made toward the development of a finite HBV treatment that achieves permanent loss of HBsAg and HBV DNA (so-called "HBV cure"), which could provide the means to eliminate HBV as a public health threat. However, the HBV cure is just one step toward achieving WHO HBV elimination targets by 2030, and much work must be done now to prepare for the successful implementation of the HBV cure. In this review, we describe the required steps to rapidly scale-up future HBV cure equitably. We present key actions required for successful HBV cure implementation, integrated within the World Health Organization (WHO) Global Health Sector Strategy (GHSS) 2022-2030 framework. Finally, we highlight what can be done now to progress toward the 2030 HBV elimination targets using available tools to ensure that we are preparing, but not waiting, for the cure.
Fulltext Arctic-adapted dogs emerged at the Pleistocene-Holocene transition

Sinding MS, Gopalakrishnan S, Ramos-Madrigal J, de Manuel M, Pitulko VV, Kuderna L, et al.

Science, 2020 06 26;368(6498):1495-1499.
PMID: 32587022 DOI: 10.1126/science.aaz8599

Although sled dogs are one of the most specialized groups of dogs, their origin and evolution has received much less attention than many other dog groups. We applied a genomic approach to investigate their spatiotemporal emergence by sequencing the genomes of 10 modern Greenland sled dogs, an ~9500-year-old Siberian dog associated with archaeological evidence for sled technology, and an ~33,000-year-old Siberian wolf. We found noteworthy genetic similarity between the ancient dog and modern sled dogs. We detected gene flow from Pleistocene Siberian wolves, but not modern American wolves, to present-day sled dogs. The results indicate that the major ancestry of modern sled dogs traces back to Siberia, where sled dog-specific haplotypes of genes that potentially relate to Arctic adaptation were established by 9500 years ago.
Fulltext Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions

Kravchenko J, Corsini E, Williams MA, Decker W, Manjili MH, Otsuki T, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S111-27.
PMID: 26002081 DOI: 10.1093/carcin/bgv033

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.
Fulltext Environmental immune disruptors, inflammation and cancer risk

Thompson PA, Khatami M, Baglole CJ, Sun J, Harris SA, Moon EY, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S232-53.
PMID: 26106141 DOI: 10.1093/carcin/bgv038

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.
Fulltext Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis

Hu Z, Brooks SA, Dormoy V, Hsu CW, Hsu HY, Lin LT, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S184-202.
PMID: 26106137 DOI: 10.1093/carcin/bgv036

One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
Fulltext The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling

Engström W, Darbre P, Eriksson S, Gulliver L, Hultman T, Karamouzis MV, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1:S38-60.
PMID: 26106143 DOI: 10.1093/carcin/bgv030

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.
Global systematic review of primary immunodeficiency registries

Abolhassani H, Azizi G, Sharifi L, Yazdani R, Mohsenzadegan M, Delavari S, et al.

Expert Rev Clin Immunol, 2020 07;16(7):717-732.
PMID: 32720819 DOI: 10.1080/1744666X.2020.1801422

INTRODUCTION: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear.
AREAS COVERED: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients.
EXPERT OPINION: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.
Fulltext The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease

Siboni S, Sozzi M, Kristo I, Boveri S, Rogers BD, De Bortoli N, et al.

United European Gastroenterol J, 2024 Jun;12(5):552-561.
PMID: 38536701 DOI: 10.1002/ueg2.12565

OBJECTIVE: A definitive diagnosis of gastroesophageal reflux disease (GERD) depends on endoscopic and/or pH-study criteria. However, high resolution manometry (HRM) can identify factors predicting GERD, such as ineffective esophageal motility (IEM), esophago-gastric junction contractile integral (EGJ-CI), evaluating esophagogastric junction (EGJ) type and straight leg raise (SLR) maneuver response. We aimed to build and externally validate a manometric score (Milan Score) to stratify the risk and severity of the disease in patients undergoing HRM for suspected GERD.
METHODS: A population of 295 consecutive patients undergoing HRM and pH-study for persistent typical or atypical GERD symptoms was prospectively enrolled to build a model and a nomogram that provides a risk score for AET > 6%. Collected HRM data included IEM, EGJ-CI, EGJ type and SLR. A supplemental cohort of patients undergoing HRM and pH-study was also prospectively enrolled in 13 high-volume esophageal function laboratories across the world in order to validate the model. Discrimination and calibration were used to assess model's accuracy. Gastroesophageal reflux disease was defined as acid exposure time >6%.
RESULTS: Out of the analyzed variables, SLR response and EGJ subtype 3 had the highest impact on the score (odd ratio 18.20 and 3.87, respectively). The external validation cohort consisted of 233 patients. In the validation model, the corrected Harrel c-index was 0.90. The model-fitting optimism adjusted calibration slope was 0.93 and the integrated calibration index was 0.07, indicating good calibration.
CONCLUSIONS: A novel HRM score for GERD diagnosis has been created and validated. The MS might be a useful screening tool to stratify the risk and the severity of GERD, allowing a more comprehensive pathophysiologic assessment of the anti-reflux barrier.
TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT05851482).
Fulltext Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Robey RB, Weisz J, Kuemmerle NB, Salzberg AC, Berg A, Brown DG, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1(Suppl 1):S203-31.
PMID: 26106140 DOI: 10.1093/carcin/bgv037

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested.
Fulltext Disruptive chemicals, senescence and immortality

Carnero A, Blanco-Aparicio C, Kondoh H, Lleonart ME, Martinez-Leal JF, Mondello C, et al.

Carcinogenesis, 2015 Jun;36 Suppl 1(Suppl 1):S19-37.
PMID: 26106138 DOI: 10.1093/carcin/bgv029

Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes.

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