Sensitive Subgroups Research Articles

The journey of patients affected by metastatic hormone receptor-positive/HER2-negative breast cancer from CDK 4/6 inhibitors to second-line treatment: A real-world analysis of 701 patients enrolled in the GIM14/BIOMETA study

PurposeThe aim of this study was to evaluate the effectiveness of CDK 4/6 inhibitors (CDK 4–6i) according to HER2 status (low/zero), and endocrine resistance/sensitivity, as well as the efficacy of second-line treatments, in a large real-world cohort. MethodsThe GIM14/BIOMETA study (NCT02284581) is a retrospective/prospective study of the Gruppo Italiano Mammella evaluating treatment patterns and survival outcomes in patients with metastatic breast cancer (MBC). We retrieved data on patients with hormone receptor-positive/HER2-negative MBC receiving first-line CDK 4/6i. ResultsAmong 3832 patients enrolled in the GIM14-BIOMETA study, 701 were eligible. At a median follow-up of 24.80 months, no significant differences were found between HER2-zero and HER2-low subgroups in terms of first-line time to treatment discontinuation (TTD) (26.16 months [IQR 12.84-NR] vs. 27.60 months [IQR 12.12–64.44], p = 0.972) or overall survival (OS) (mOS>60 months for both groups, p = 0.398). Median TTD was 33.24 months (IQR 16.32-NR) for the endocrine sensitive subgroup, 19.92 months (IQR 8.88–51.24) for the secondary endocrine resistant subgroup and 17.40 months (IQR 7.44–24.72) for the primary endocrine resistant subset, respectively (p < 0.001). Among 239 patients receiving second-line treatment, no significant difference (p = 0.188) was found in terms of second-line TTD between those treated with capecitabine (6.11 months, IQR 2.96–11.47), taxane-based chemotherapy (5.06 months, IQR 2.99–9.99), everolimus plus exemestane (5.39 months, IQR 2.53–9.03) or fulvestrant (6.44 months, IQR 3.38-NR). ConclusionsEndocrine therapy plus CDK 4/6i represents an effective treatment, regardless of HER2 status (low/zero). Second-line agents did not differ significantly in terms of TTD. Endocrine resistant cancers exhibit poor response to CDK 4/6i.

Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis

The integrated stress response (ISR) enables cells to cope with a variety of insults, but its specific contribution to downstream cellular outputs remains unclear. Using a synthetic tool, we selectively activate the ISR without co-activation of parallel pathways and define the resulting cellular state with multi-omics profiling. We identify time- and dose-dependent gene expression modules, with ATF4 driving only a small but sensitive subgroup that includes amino acid metabolic enzymes. This ATF4 response affects cellular bioenergetics, rerouting carbon utilization towards amino acid production and away from the tricarboxylic acid cycle and fatty acid synthesis. We also find an ATF4-independent reorganization of the lipidome that promotes DGAT-dependent triglyceride synthesis and accumulation of lipid droplets. While DGAT1 is the main driver of lipid droplet biogenesis, DGAT2 plays an essential role in buffering stress and maintaining cell survival. Together, we demonstrate the sufficiency of the ISR in promoting a previously unappreciated metabolic state.

Self-assessed threshold for cold temperatures and thermal insulation of clothing among poultry workers

The association between self-assessed cold threshold (CT) and thermal insulation of clothing (Icl) was analysed in 283 poultry workers in Thailand. The mean CT was 13.5 °C (range − 28–29) and the mean Icl was 1.23 clo (range 0.35–2.21). The adjusted CT remained unchanged at low Icls (0.35 through 1.25 clo) but was estimated to increase by 14.8 °C at high Icls (1.25 through 2.21 clo). Overall, CT was higher by 2.4 °C (95% confidence interval [CI] 0.3–3.8) at high (≥ 1.25 clo) than that at low (< 1.25 clo) Icl, but this difference was modified by personal and work-related factors. The difference was 2.6 °C (CI 0.5–4.6) for older (30–57 y) compared to younger (18–29 y) participants, with an excess of 7.3 °C (CI 5.6–9.0) for low vs high educated participants, 2.6 °C (CI 0.5–4.8) for those doing heavy vs light work, 7.4 °C (CI 3.7–11.0) for alcohol consumers vs others, and 3.4 °C (CI 0.6–6.3) for smokers vs non-smokers. The differences were independent of personal characteristics and worksite physical conditions and were interpreted as increased cold sensitivity among subgroups with lesser stamina and poorer health. Sensitive worker subgroups should be identified, and their need for cold protection should be reviewed.

Abstract P105: Comparative Effectiveness between Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors on Mortality: a Nationwide, Population-based, Prospective Cohort Study in China

Background: Contemporary evidence comparing the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin II receptor blockers (ARBs) on long-term outcomes in patients with hypertension is sparse and inconsistent. The aim is to compare the effectiveness of ACEI monotherapy versus ARB monotherapy on all-cause death and cardiovascular death. Methods: Based on a nationwide, population-based prospective cohort project, which covered 318 study sites from 2014 to 2021 in China. Detailed information was collected by questionnaire, physical measurement, and blood test. Participants aged 35-75 years with hypertension and taking ACEI or ARB monotherapy once daily, and with good medication adherence at baseline were included. Information on mortality was followed up until 31 December 2021. Stabilized inverse probability treatment weighting (IPTW) was applied to compare the effectiveness. Results: 68 771 (49326 ARB, 19445 ACEI) participants were finally included, with a mean age of 59.9±8.3 years and 40.2% being female. During a median follow-up time of 44 months, 785 cardiovascular deaths and 1657 deaths were recorded. Compared with ACEI monotherapy, ARB monotherapy was associated with a quarter relative risk reduction of cardiovascular death (IPTW rates: 0.95 % Vs 1.43%, HR =0.73 [ 95%CI , 0.62-0.87]) and one-fifth relative risk reduction of all-cause death (IPTW rates: 2.13% Vs 2.84%, HR =0.80 [ 95%CI , 0.71-0.89]). These differences remained consistent after further adjusting for blood pressure and with differences more pronounced in patients with controlled and newly onset hypertension. Sensitive analysis and subgroup analysis yielded consistent results. Conclusions: Attention should be paid that ARB can be preferred to ACEI in patients with hypertension in terms of long-term health outcomes. Funding: This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2021-I2M-1-011), and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4, NCRCSZ-2023-016). Keywords: Hypertension, Angiotensin receptor blocker, Angiotensin-converting enzyme inhibitor, Mortality, Comparative effectiveness

Association of systemic immune-inflammation index with asthma and asthma-related events: a cross-sectional NHANES-based study.

Asthma is associated with persistent airway inflammation, and numerous studies have investigated inflammatory markers causing asthma. However, the systemic immune-inflammation index (SII) is a novel inflammatory marker, with scarce research reporting on the correlation between SII and asthma and asthma-related events. The purpose of this study was to assess the relationship between SII and asthma and asthma-related events (including whether asthma is still present, asthma flare-ups in the past year, and asthma duration) using data from the National Health and Nutrition Examination Survey (NHANES). The study utilized data from NHANES 2009-2018 with asthma and asthma-related events as dependent variables and SII as an independent variable. Multifactor logistic regression was employed to assess the correlation between the independent and dependent variables. Smoothed curve-fitting and threshold effect analyses were also carried out to determine the presence of non-linear relationships. Subgroup analyses were then performed to identify sensitive populations. In this study, we analyzed data from 40,664 participants to elucidate the association between SII and asthma and its related events. The study findings indicated a positive correlation between SII and asthma, with a relative risk increase of 0.03% for asthma incidence per one percentage point increase in SII (OR = 1.0003, 95% CI: 1.0002, 1.0004). For individuals still suffering from asthma, higher SII also indicated a positive correlation with ongoing asthma (OR = 1.0004, 95% CI: 1.0001, 1.0006). However, no statistically significant association was observed between SII and asthma exacerbations within the following year (OR = 1.0001, p > 0.05). When considering the duration of asthma, we observed a slight positive correlation with SII (β = 0.0017, 95% CI: 0.0005, 0.0029). Additionally, a significant non-linear relationship between SII and asthma duration emerged at the threshold of 504.3 (β = 0.0031, 95% CI: 0.0014-0.0048, p = 0.0003). Subgroup analysis revealed a stronger correlation between SII and asthma in male patients (OR = 1.0004, 95% CI: 1.0002-1.0006) and individuals aged 60 and above (OR = 1.0005, 95% CI: 1.0003-1.0007). No gender differences were observed for individuals still suffering from asthma. However, the positive correlation between SII and asthma was more pronounced in participants under 20 years old (OR = 1.0004 in Model 3, 95% CI: 1.0002-1.0006). Specific sensitive subgroups for asthma exacerbation recurrence within the past year were not identified. When considering asthma duration, we observed this association to be significant in male individuals (β = 0.0031 in Model 3, 95% CI: 0.0014-0.0049) as well as individuals aged 20 to 39 (β = 0.0023 in Model 3, 95% CI: 0.0005-0.0040). Our study concludes that SII is positively correlated with the persistence of asthma yet has limited predictive power for asthma recurrence. This highlights SII's potential as a tool for assessing asthma risk and formulating targeted management strategies.

Abstract PO-031: Systematic discovery of chemotherapy response biomarkers in Peripheral T Cell Lymphomas

Abstract Background. Identifying which patients will benefit from individual therapies remains a general challenge in oncology. Predictive biomarkers of drug sensitivity, when known, can increase the rate of success of trials, and allow stratification of patients for targeted combination therapies, as recent shown by the GUIDANCE-01 trial in Large B-Cell Lymphoma. Peripheral T-Cell Lymphomas (PTCL) could particularly benefit from this approach, being heterogeneous diseases against which many therapies are active in unpredictable subsets of patients. A central challenge of biomarker discovery is finding true determinants of drug response, which may be multiple genes, among thousands of molecular features that may accidentally correlate. Here, we aim to mitigate this challenge by combining functional genetic screens and gene expression profiling in diverse PTCL cultures, to enable the systematic discovery of drug sensitivity biomarkers. Methods. To discover genes whose expression directly modifies drug sensitivity, we conducted genome-wide CRISPR screens with PTCL cells under treatment with five therapies with clinical activity in PTCL: Romidepsin, Pralatrexate, Gemcitabine, Oxaliplatin, and Bortezomib. To discover genes whose basal expression significantly correlates with specific drug sensitivities, we measured RNAseq and drug response functions for a diverse panel of 27 PTCL cultures. Genes in the intersection of both experiments are causally related to and correlate with drug responses in PTCL, and have the statistical benefit of detection by independent methods. Results. Functional genetic screens on therapy provided mechanistic insights for each drug of interest, and identified genes whose perturbation affects drug sensitivity. Whereas hundreds of genes nominally correlate with drug sensitivity in cell line panels, for each drug a shortlist of only 5 to 20 genes are both CRISPR hits and correlate with response across PTCL cultures. For each drug tested, multi-gene sensitivity scores constructed from hits stratify PTCL cultures into statistically distinct sensitive and non-sensitive subgroups (Mann Whitney P-Values &amp;lt;0.01). These genes’ relationships to drug mechanisms were often supported by prior studies, including functions in DNA repair, cell cycle regulation, and solute carriers required for cellular entry of specific therapies, such as SLC19A1 for Pralatrexate and SLC43A2 for Oxaliplatin. Conclusions. Combining functional genetic screens and correlative drug sensitivity measurements narrowed the search for predictive biomarkers of drug sensitivity, and may be a general means of refining biomarker hypotheses for validation in clinical datasets. Although chemotherapy sensitivity is commonly polygenic, multi-gene scores based on few mechanistically-related genes were able to significantly distinguish drug sensitive from resistant PTCLs. These approaches provide novel hypotheses for drug-gene relationships that may serve as the basis for molecular subtyping of individual lymphomas for precision regimens. Citation Format: Adam C Palmer, Jacob C Pantazis. Systematic discovery of chemotherapy response biomarkers in Peripheral T Cell Lymphomas [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-031.

Molecular profiling after short-term preoperative endocrine therapy to identify oestrogen receptor positive (ER+)/HER2+ early breast tumours with favourable prognosis.

560 Background: The impeded anti-proliferative response of Estrogen Receptor positive (ER+) HER2+ breast cancer (BC) to endocrine therapy (ET) has been considered negated by treatment with anti-HER2 therapies but residual disease after anti-HER2 therapy remains at risk of recurrence. Studying the molecular changes (MolC) of ER+HER2+ BC in response to ET will provide clinical insights to treatment options. Methods: POETIC was a phase III trial of post-menopausal patients with ER+ BC randomized 2:1 to 2-weeks of peri-operative aromatase inhibitors (POAI) vs control, followed by standard-of-care. Paired pre-treatment (B) and on-treatment (2wk) samples from 313 ER+HER2+ BC (213 POAI/100 controls) were gene expression profiled (BC 360 codeset; NanoString). Association of MolC with Early biological response to AI was assessed by residual Ki672wk (low ≤10%; high &gt;10%) by T-test, multiple testing corrected by Benjamini &amp; Hochberg (FDR); with time to recurrence (TTR) was estimated using multivariable Cox regression models adjusted for post-surgery clinicopathological variables and age as adjuvant treatment surrogate. Results: In POAI tumours, immunity-related signatures and mammary stemness were significantly upregulated in responders while proliferation, DNA-damage repair (DDR), TP53mutational status and ER-signaling were downregulated (FDR&lt;0.05). Controls had exclusive downregulation of PDL1 and upregulation of hypoxia (FDR &lt; 0.05). We previously identified 5 new molecular subgroups based on baseline gene expression (1- Immune high, ESR1 low; 2- ECM, ESR1 low, highest ERBB2; 3- DDR deficiency, 4- Endocrine signalling high and 5- Endocrine and PI3K/MAPK/RAS signalling high) which were associated with different response to AI and differential outcome. Endocrine-signalling, PI3K/MAPK/RAS signalling, tumour-immunity and chemokines were upregulated at a higher magnitude in AI sensitive subgroups (3 and 4) while the molecular subgroup with early resistance to AI and poorer outcome at baseline (2) did not show significant changes. Intrinsic subtype (IS) shifting was significantly more prevalent in treated (37%, 79/213) than in controls (14%, 14/100) (p &lt;0.001). In POAI most Luminal B (LumB) shifted to Luminal A (LumA; 79%, 59/75), driven by a reduction in proliferation. LumA2wk was associated with better outcome compared to LumB2wk (HR 0.2; CI95% 0.06-0.72, p=0.01). IS2wk provides additional information predicting TTR, than ISB (AIC value = 217.2 vs 221.6). Conclusions: We provide a comprehensive picture on how ER+HER2+ BC gene expression profile changes in response to ET. Most LumB BC shift to LumA, being LumA2wk IS significantly associated with better outcome. There is a clinical utility of peri-operative ET for ER+HER2+ BC, guiding who would have good prognosis for adjuvant ET and who may need additional therapy. Clinical trial information: NCT02338310 .

Efficacy and safety of a panthenol-enriched mask for individuals with distinct impaired skin barrier subtypes.

The protection for different skin types with impaired skin barrier in the market is insufficient. To evaluate the efficacy and safety of a panthenol-enriched mask (La Roche-Posay Mask Pro) in addressing various skin barrier impairment subgroups, including dry sensitive, oily sensitive, and oily acne skin. A total of 177 participants were enrolled in the study and divided into three subgroups based on their skin type. Participants used the mask following the specified protocol, with measurements taken for skin hydration, transepidermal water loss (TEWL), sebum content, and skin redness-factors that are directly influenced by skin barrier function. Assessments were conducted at baseline and after 1 day (tested 15 min post-application), 7 days, and 14 days of application using Sebumeter, Tewameter, Corneometer, Mexameter, and VISIA. Results showed significant improvements in skin parameters across all subgroups. In the dry sensitive skin subgroup, the mask increased skin hydration, sebum content, and reduced redness. For the oily sensitive skin subgroup, the mask regulated sebum production and improved skin hydration. In the oily acne skin subgroup, the mask reduced sebum content, redness, TEWL, and post-inflammatory erythema and hyperpigmentation. Tolerance was excellent for all skin types, with no adverse reactions observed. This study highlights the efficacy and safety of the panthenol-enriched LRP Mask Pro for individuals with distinct skin barrier impairment subgroups. The mask's versatile formulation and proven efficacy make it a valuable skincare product for addressing various skin concerns and achieving healthier, more balanced skin.

The impact of long-term PM1 exposure on all-cause mortality and its interaction with BMI: A nationwide prospective cohort study in China

BackgroundChina has a serious air pollution problem and a high prevalence of obesity. The interaction between the two and its impact on all-cause mortality is a public health issue of great concern. ObjectivesThis study aimed to investigate the association between long-term exposure to particulate matter with aerodynamic diameter ≤ 1 μm (PM1) and all-cause mortality, as well as the interaction effect of body mass index (BMI) in the association. MethodsA total of 33,087 participants from 162 counties in 25 provinces in China were included, with annual average PM1 exposure being estimated based on the county address. The PM1-mortality relation was evaluated using the time-varying Cox proportional hazards models, with the dose-response relationship being fitted using the penalized splines. Besides, the potential interaction effect of BMI in the PM1-mortality relation was evaluated. ResultsThe incidence of all-cause deaths was 76.99 per 10,000 person-years over a median of 8.2 years of follow-up. After controlling for potential confounders, the PM1-mortality relation was approximately J-shaped. The full-adjustment analysis observed the hazard ratio (HR) of all-cause mortality was 1.114 [95 % confidence interval (CI): 1.017–1.220] corresponding to a 10 μg/m3 rise in PM1 concentration. Further stratified analyses suggested the adverse effects of PM1 might be more pronounced among the underweight. DiscussionHigher PM1 concentrations were associated with an increase in all-cause mortality. The BMI might further alter the relation, and the underweight population was the sensitive subgroup of the population that needed to be protected.

Differential c-Fos Response in Neurocircuits Activated by Repeated Predator Stress in Male and Female C57BL/6J Mice with Stress Sensitive or Resilient Alcohol Intake Phenotypes

Comorbidity of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) worsens the prognosis for each of these individual disorders. The current study aimed to identify neurocircuits potentially involved in regulation of PTSD-AUD comorbidity by mapping expression of c-Fos in male and female C57BL/6J mice following repeated predator stress (PS), modeled by exposure to dirty rat bedding. In experiment 1, the levels of c-Fos in the paraventricular nucleus of the hypothalamus (PVH) and the nucleus accumbens shell were higher after the second PS vs the first PS, indicating a sensitized response to this stressor. Additional brain regions showed varied sex-dependent and independent regulation by the two consecutive PS exposures. In experiment 2, mice that increased voluntary alcohol consumption following four exposures to PS (Sensitive subgroup) showed higher c-Fos induction in the PVH, piriform cortex and ventromedial hypothalamus than mice that decreased consumption following these exposures (Resilient subgroup). In contrast to these brain regions, c-Fos was higher in the anterior olfactory nucleus of Resilient vs Sensitive mice. Taken together, these data demonstrate that repeated PS exposure and voluntary alcohol consumption increase neuronal activity across neurocircuits in which specific components depend on the vulnerability of individual mice to these stressors. Increased PVH activity observed across both experiments suggests this brain area as a potential mediator of PS-induced increases in alcohol consumption. Future investigations of specific neuronal populations within the PVH activated by PS, and manipulation of these specific neuronal populations, could improve our understanding of the mechanisms leading to PTSD-AUD comorbidity.

Association of Fine Particulate Matter and Its Components with Macrosomia: A Nationwide Birth Cohort Study of 336 Chinese Cities.

To examine the associations between macrosomia risk and exposure to fine particulate matter (PM2.5) and its chemical components during pregnancy, we collected birth records between 2010 and 2015 in mainland China from the National Free Preconception Health Examination Project and used satellite-based models to estimate concentrations of PM2.5 mass and five main components, namely, black carbon (BC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+). Associations between macrosomia risk and prenatal exposure to PM2.5 were examined by logistic regression analysis, and the sensitive subgroups were explored by stratified analyses. Of the 3,248,263 singleton newborns from 336 cities, 165,119 (5.1%) had macrosomia. Each interquartile range increase in concentration of PM2.5 during the entire pregnancy was associated with increased risk of macrosomia (odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.17-1.20). Among specific components, the largest effect estimates were found on NO3- (OR = 1.36; 95% CI, 1.35-1.38) followed by OC (OR = 1.23; 95% CI, 1.22-1.24), NH4+ (OR = 1.22; 95% CI, 1.21-1.23), and BC (OR = 1.21; 95% CI, 1.20-1.22). We also that found boys, women with a normal or lower prepregnancy body mass index, and women with irregular or no folic acid supplementation experienced higher risk of macrosomia associated with PM2.5 exposure.

Plasma Cyclooxygenase-2 as a Potential Biomarker for Early Diagnosis of Kawasaki Disease

Background: Previous research demonstrated the association between cyclooxygenase-2 (COX-2) gene polymorphisms and susceptibility to Kawasaki disease (KD). This study aims to detect the plasma concentration of COX-2 in different phases of KD patients and evaluate the relationship between COX-2 level and coronary artery lesion formation, therapeutic response to intravenous immunoglobulin. Methods: Plasma COX-2 levels were measured by enzyme-linked immunosorbent assay in KD patients during the acute (a-KD, n = 52), subacute (s-KD, n = 46), and convalescent (c-KD, n = 43) phase. Results: The concentration of COX-2 in the a-KD group was significantly higher than that in the s-KD, c-KD, healthy control or febrile control group, respectively. There was no difference in the levels of COX-2 between the KD with or without coronary artery lesion subgroups, intravenous immunoglobulin resistant, and sensitive subgroups in the a-KD group, respectively. Conclusions: The plasma concentration of COX-2 might be a novel potential biomarker of acute KD.

Initial training of teachers for the education of students from social welfare institutions in an inclusive school

Students from social care institutions are a sensitive subgroup whose inclusive needs often diverse the average student’s needs and for which specific teachers’ competencies are expected. The paper presents the special educational needs of this heterogeneous group of school children explaining the frequent occurrence of learning difficulties, behavioral, emotional, and other developmental problems conditioned by unfavorable educational, social, economic, and cultural factors. The valid available online study programs of faculties for future teachers for mandatory elementary school subjects and classroom teachers at the faculties of two universities in the Republic of Croatia were analyzed. The goal of the research was to determine the number of subjects aimed at teaching students with disabilities during the initial future teachers’ education and the occurrence of topics of students with disabilities education in the subjects that form the basis of future teacher practice, subjects for the acquisition of didactic-methodical, psychological, pedagogical, social, and practical teaching competencies. The obtained results can serve as a predictor for future research and the basis for creating programs for professional development in inclusive teaching based on the objective needs of individual teaching professions.

PFAS levels and exposure determinants in sensitive population groups

BackgroundPer- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants. The first exposure to PFAS occurs in utero, after birth it continues via breast milk, food intake, environment, and consumer products that contain these chemicals. Our aim was to identify determinants of PFAS concentrations in sensitive population subgroups– pregnant women and newborns. MethodsNine European birth cohorts provided exposure data on PFAS in pregnant women (INMA-Gipuzkoa, Sabadell, Valencia, ELFE and MoBa; total N = 5897) or newborns (3xG study, FLEHS 2, FLEHS 3 and PRENATAL; total N = 940). PFOS, PFOA, PFHxS and PFNA concentrations were measured in maternal or cord blood, depending on the cohort (FLEHS 2 measured only PFOS and PFOA). PFAS concentrations were analysed according to maternal characteristics (age, BMI, parity, previous breastfeeding, smoking, and food consumption during pregnancy) and parental educational level. The association between potential determinants and PFAS concentrations was evaluated using multiple linear regression models. ResultsWe observed significant variations in PFAS concentrations among cohorts. Higher PFAS concentrations were associated with higher maternal age, primipara birth, and educational level, both for maternal blood and cord blood. Higher PFAS concentrations in maternal blood were associated with higher consumption of fish and seafood, meat, offal and eggs. In cord blood, higher PFHxS concentrations were associated with daily meat consumption and higher PFNA with offal consumption. Daily milk and dairy consumption were associated with lower concentrations of PFAS in both, pregnant women and newborns. ConclusionHigh detection rates of the four most abundant PFAS demonstrate ubiquitous exposure of sensitive populations, which is of concern. This study identified several determinants of PFAS exposure in pregnant women and newborns, including dietary factors, and these findings can be used for proposing measures to reduce PFAS exposure, particularly from dietary sources.

Effects of perchlorate, nitrate, and thiocyanate exposures on serum total testosterone in children and adolescents

Perchlorate, nitrate, and thiocyanate are common thyroid disruptors in daily life and alter testosterone levels in animals. However, little is known about the effects of perchlorate, nitrate, and thiocyanate on serum total testosterone (TT) in the general population. The study was designed to assess the associations between urinary levels of perchlorate, nitrate, and thiocyanate and serum total testosterone (TT) in the general population. The present study utilized data from the 2011–2016 National Health and Nutritional Examination Survey (NHANES). A total of 6201 participants aged 6–79 with information on urinary perchlorate, nitrate, thiocyanate, and serum total testosterone were included. We conducted multiple linear regression models and Bayesian Kernel Machine Regression (BKMR) models to estimate the associations by sex-age groups. Children (ages 6–11) have higher levels of perchlorate and nitrate than the rest. After adjusting for covariates, urinary perchlorate was significantly negatively associated with serum TT in male adolescents (β = −0.1, 95 % confidence interval: −0.2, −0.01) and female children [−0.13, (−0.21, −0.05)]. Urinary nitrate was significantly negatively associated with serum TT in female children, while urinary thiocyanate was significantly positively associated with serum TT in female adults aged 20 to 49 [0.05 (0.02, 0.08)]. BKMR analysis indicated that no other interactions were found between urinary perchlorate, nitrate, and thiocyanate. Our findings suggested that urinary perchlorate, nitrate, and thiocyanate levels may relate to serum total testosterone levels in specific sex-age groups. We identified male adolescents and female children as are most sensitive subgroups where testosterone is susceptible to interference.

Clinical significance of T cell receptor repertoire in primary Sjogren's syndrome.

SummaryBackgroundPrimary Sjogren's syndrome (SS) is a chronic inflammatory disease with unknown aetiology. Although clonal expansion of autoreactive T cells has been identified in patients with SS, the clinical correlation of T-cell receptor (TCR) variance in SS remains unclear.MethodsTCRβ repertoire sequencing was performed on 260 SS patients with 3-6 months of follow-up in a cohort study to dynamically assess the characteristics of TCR diversity and their clinical significance.FindingsWe found that SS patients had lower TCR diversity, but higher frequency of public clones than healthy controls (HCs). Significant differences were identified in the usage of the variable (V) gene, joining (J) gene, and V-J pairing between SS and HCs. Eighteen SS-associated clones were identified, showing a high sensitivity and specificity for disease classification. TCR diversity was correlated with the presence of dental caries, thrombocytopenia, hepatocholangeitis, antinuclear antibody, anti-SSA/SSB, and hypergammaglobulinemia but not with disease course, number of relapses, arthritis, rheumatoid factor, hypocomplementemia or disease activity defined by SSDAI. During follow-up, the TCR abnormalities remained, represented by more altered V/J usage and higher frequencies of SS-associated clones. Among SS patients, the sensitive subgroup had increased TCR diversity after treatment. Eighty-five SS-sensitivity associated TCRs were identified and used for sensitivity classification by cross validation with high specificity and sensitivity.InterpretationThese results demonstrate that the TCR repertoire could provide insights into the disease status and prognosis in SS and other autoimmune diseases.FundingThis study was funded by the National Key Research and Development Program of China (2016YFC0906201), Sichuan Science and Technology Program (2020YJ0223), and the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18015).

Primary analysis from the phase 2 study of continuous talazoparib (TALA) plus intermittent low-dose temozolomide (TMZ) in patients with relapsed or refractory extensive-stage small cell lung cancer (ES-SCLC).

8517 Background: TALA exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. TMZ has been shown to increase antitumor response when combined with TALA in SCLC models (Wainberg AACR 2016). TALA plus TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes. Methods: This is a phase 2, open-label, single-arm study of the safety and efficacy of TALA plus TMZ in patients with ES-SCLC, relapsed or refractory to a first-line platinum-based regimen. Participants receive TALA 0.75 mg (or 0.5 mg if creatinine clearance &lt; 60 mL/min) po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria, versus a historical control of 15% ORR in second-line topotecan, with the null hypothesis rejected for 8 or more confirmed responses among 28 evaluable subjects (29% ORR). Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as status of DNA damage response genes (DDR) and patient reported outcomes. A Simon two-stage design was utilized to reach a total accrual of 28 evaluable patients. Results: Thirty-one subjects were enrolled, of which 3 were non-evaluable due to ineligibility (1) or early withdrawal of consent prior to first disease assessment (2). Eleven of 28 evaluable subjects (39.3%) achieved a confirmed partial response. The ORR was similar among platinum-refractory (3/6), -resistant (4/9), and -sensitive subgroups (4/13). The median time to response was 1.8 months (m), duration of response 5.8 m, progression free survival 4.5 m, and overall survival 11.9 m. Adverse events (AEs) were manageable, with grade ≥ 3 AEs being thrombocytopenia (61.3%), anemia (54.8%), neutropenia (41.9%), and atypical pneumonia (3.2%), which responded well to dose-hold or dose-reduction and transfusion or growth factor support as needed. Cell free DNA and tissue analysis demonstrated no germline DDR mutations among the trial subjects, but somatic DDR mutations at baseline and acquired during treatment were common. Three subjects remain on study treatment. Conclusions: The study exceeded its target response rate. This is the second trial to demonstrate a benefit of PARP inhibition with low-dose TMZ in SCLC (see Farago Cancer Discovery 2019). A phase 3 study is appropriate to confirm the benefit of this approach compared to currently approved options. Clinical trial information: NCT03672773.

The impact of induction chemotherapy response to survival outcomes in oropharyngeal cancer.

6040 Background: The role of induction chemotherapy (IC) in oropharyngeal squamous cell carcinoma (OPSCC) remains inconclusive. Previous randomized trials showed no survival advantage with IC in head and neck squamous cell carcinoma, including OPSCC. However, the impact of response to IC has rarely been considered in these trials. In this study, we aimed to investigate the prognostic value of IC response on HPV+ and HPV- OPSCC. Methods: Patients with stage II-IVB OPSCC (UICC 7 th edition) who underwent IC (paclitaxel and platinum-based regimen for the most) and concurrent chemoradiotherapy during 2010 to 2020 were enrolled. HPV status was confirmed by p16 immunohistochemistry (p16 ≥ 70%). The clinical response to IC was assessed on MRI or CT images. Patients with complete response (CR) or major partial response (PR) (≥50% PR) were defined as sensitive subgroup (IC-s), while those with &lt;50% PR, stable disease (SD) or progressive disease (PD) were deemed as resistant (IC-r). Progression-free survival (PFS) and overall survival (OS) were compared. Results: 51 HPV+ and 57 HPV- OPSCC patients were included. In the entire cohort, 55.6% patients were sensitive to IC. HPV+ OPSCC showed higher IC-s rate (62.7% vs. 49.1%) than HPV- subgroup. IC-s was associated with better clinical outcomes either in the whole cohort (3y-PFS 91.7%vs.43.7%, P &lt; 0.001; 3y-OS 98.3% vs.67.4%, P = 0.002), the HPV+ subgroup (3-year PFS 94.7% vs. 47.9%, P &lt; 0.001; 3-year OS 100% vs. 73.5%, P = 0.055) or the HPV- subgroup (3-year PFS 88.2% vs. 40.9%, P = 0.001; 3-year OS 96.4% vs. 63.1%, P = 0.026). Multivariate analysis demonstrated IC-s as an independent prognosticator for 3y-PFS (hazard ratio [HR], 0.088; 95% confidence interval [CI], 0.027-0.289; P &lt; 0.001) and 3y-OS ([HR], 0.100; 95% CI, 0.021-0.477; P = 0.004) when adjusting for T, N, gender, age and smoking status. Conclusions: The response to IC exerts a critical predictive effect on survival outcomes in both HPV+ and HPV- OPSCC. Personalized treatment strategy based on IC response warrants further exploration in future studies. Response to induction chemotherapy. All patients (n = 108) HPV+ patients (n = 51) HPV- patients (n = 57) OP LN OP+LN OP LN OP+LN OP LN OP+LN IC-s, n (%) 84 (77.8%) 64 (59.3%) 60 (55.6%) 44 (86.3%) 34 (66.7%) 32 (62.7%) 40 (70.2%) 30 (52.6%) 28 (49.1%) CR 45 (41.7%) 21 (19.4%) 12 (11.1%) 26 (51.0%) 13 (25.5%) 7 (13.7%) 19 (33.3%) 8 (14.0%) 5 (8.8%) Major PR 39 (36.1%) 43 (39.8%) 48 (44.4%) 18 (35.3%) 21 (41.2%) 25 (49.0%) 21 (36.8%) 22 (38.6%) 23 (40.4%) IC-r, n (%) 24 (22.2%) 44 (40.7%) 48 (44.4) 7 (13.7%) 17 (33.3) 19 (37.3%) 17 (29.8) 27 (47.4%) 29 (50.9%) Minor PR 14 (13.0%) 18 (16.7%) 20 (18.5%) 2 (3.9%) 5 (9.8%) 5 (9.8%) 12 (21.1%) 13 (22.8%) 15 (26.3%) SD 9 (8.3%) 25 (23.1%) 27 (25.0%) 5 (9.8%) 12 (23.5%) 14 (27.5%) 4 (7.0%) 13 (22.8%) 13 (22.8%) PD 1 (0.9%) 1 (0.9%) 1 (0.9%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (1.8%) 1 (1.8%) 1 (1.8%) Abbreviation: OP = oropharynx; LN = lymph node; ORR = objective response rate.

A case-control study of polychlorinated biphenyl association with metabolic and hormonal outcomes in polycystic ovary syndrome

Polychlorinated biphenyls (PCBs) are a class of environmental pollutants with a long half-life that sequester in fat. Women with polycystic ovarian syndrome (PCOS) may represent a sensitive subgroup to endogenous exposure to PCBs because of associated weight gain. Seven PCB congeners were compared in age, ethnicity, and BMI matched women with (n = 29) and without (n = 30) PCOS and related to metabolic outcomes, and steroid and thyroid hormone levels. PCB118, PCB138, PCB153, and PCB180 were detected in all serum samples but geometric mean did not differ between cases and controls. PCBs correlated with increasing concentrations of each other (p < .01), increasing age (p < .01) and decreasing lneGFR (p < .05). lnPCB118 correlated with increasing Free-T4 (p = .028). lnPCB158, lnPCB180, and ln∑PCB correlated with increasing lnSHBG (p = .044). In regression modeling, although not significant, PCB118 positively associated with lnSHBG in controls (p = .0504) but not in cases; estradiol inversely associated with PCB138 in controls (p = .055) and ∑PCB in cases (p = .051). No significant associations were observed between metabolic endpoints, and steroid and thyroid hormone levels. The results presented do not suggest the PCOS cases in this cohort are at adverse risk compared to age, ethnicity, and BMI matched controls.

Mucosal drug delivery and 3D printing technologies: A focus on special patient populations.

In the last decade, additive manufacturing (AM) technologies have revolutionized how healthcare provision is envisioned. The rapid evolution of these technologies has already created a momentum in the effort to address unmet personalized needs in large patient groups, especially those belonging to sensitive subgroup populations (e.g., paediatric, geriatric, visually impaired). At the same time, AM technologies have become a salient ally to overcome defined health challenges in drug formulation development by addressing not only the requirement of personalized therapy, but also problems related to lowering non-specific drug distribution and the risk of adverse reactions, enhancing drug absorption and bioavailability, as well as ease of administration and patient compliance. To this end, mucoadhesive drug delivery systems fabricated with the support of AM technologies provide competitive advantages over conventional dosage forms, aiming to entice innovation in drug formulation with special focus on sensitive patient populations.