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Novel geometrically asymmetric biscinnamyl-sulfone compounds (6a-c) with donor-π-conjugated spacer-acceptor functionality were successfully synthesized. This was achieved by coupling cinnamaldehyde precursors with 3,3'-diaminodiphenyl sulfone in dry organic solvents, resulting in high yields. Several spectroscopic techniques were employed to identify the derivatives. The absorption spectra of these compounds exhibited broad bands that spanned up to 120 nm, which can be attributed to their extended conjugation systems. In order to explore the electronic transitions of these materials, Time-Dependent Density-Functional Theory (TD-DFT) with EIFPCM solvation mode was utilized. We computationally investigated the static nonlinear optical (NLO) parameters, including dipole moments (µ), polarizability (α), anisotropic polarizability (Δα), first-order hyperpolarization (ß), and second-order hyperpolarization (γ). Although the new structures possess different functional groups, they displayed similar electronic potentials when their molecular electrostatic potentials were plotted. These potentials are crucial in stabilizing the molecules in crystal systems through noncovalent forces such as C-H⋯π stacking and hydrogen bonding. They also provide insights into the electronic assessments and energetics of these individual forces. By estimating the frontier orbitals, we gained an understanding of the intramolecular charge transfer in the compounds. Energy gap values were determined using the orbitals of density of states method and experimentally via the Tauc method. The computational and experimental results were in good agreement. Lastly, we examined the influence of different protic and aprotic solvents on the absorption bands of compound 6b, as an example. This compound showed a significant bathochromic shift of 41 nm upon changing the solvent from acetic acid to dimethyl sulfoxide.

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Researchers have recently shown a great deal of interest in molybdenum diselenide (MoSe2)-based solar cells due to their outstanding semiconducting characteristics. However, discrepancies in the band arrangement at the MoSe2/ETL (electron transport layer) and hole transport layer (HTL)/MoSe2 interfaces impede performances. In this research, a device combination with Ag/FTO/ETL/MoSe2/HTL/Ni is employed, where 7 HTLs and 3 different ETLs have been utilized to explore which device arrangement is superior. To achieve the most effective device arrangement, the effects of various device variables, such as thickness, donor density, acceptor density, defect density, temperature, series, and shunt resistance, are optimized. The computational evaluation under AM 1.5 light spectrums (100 mW/cm2) is performed using the SCAPS-1D simulator. When the several device parameters were optimized, the device that was correlated with Ag/FTO/SnS2/MoSe2/V2O5/Ni revealed the highest overall performances among the three different ETL (In2S3, SnS2, ZnSe)-based devices, with measuring a PCE of 34.07 %, a VOC of 0.918 V, a JSC of 42.565 mAcm-2, and an FF of 87.19 %. This recommended MoSe2-based solar cell exhibits outstanding efficiency in terms of maintenance and comparison to numerical thin film solar cells, highlighting MoSe2 as an attractive option for solar energy systems while eliminating toxicity challenges.

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Caenorhabditis elegans males undergo sex-specific tail tip morphogenesis (TTM) under the control of the DM-domain transcription factor DMD-3. To find genes regulated by DMD-3, We performed RNA-seq of laser-dissected tail tips. We identified 564 genes differentially expressed (DE) in wild-type males vs. dmd-3(-) males and hermaphrodites. The transcription profile of dmd-3(-) tail tips is similar to that in hermaphrodites. For validation, we analyzed transcriptional reporters for 49 genes and found male-specific or male-biased expression for 26 genes. Only 11 DE genes overlapped with genes found in a previous RNAi screen for defective TTM. GO enrichment analysis of DE genes finds upregulation of genes within the unfolded protein response pathway and downregulation of genes involved in cuticle maintenance. Of the DE genes, 40 are transcription factors, indicating that the gene network downstream of DMD-3 is complex and potentially modular. We propose modules of genes that act together in TTM and are coregulated by DMD-3, among them the chondroitin synthesis pathway and the hypertonic stress response.

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This study was developed to evaluate the removal potential of ibuprofen, naproxen and 17-ß-estradiol in artificial wetlands constructed on a laboratory scale, using eight experimental devices planted with L. octovalvis species, tested with gravel substrate and without gravel substrate, which were fortified with synthetic mixtures at concentrations of 1, 2 and 5 mg/L of the three compounds, during a batch exposure time of nine days. The removal efficiency for 17-ß-estradiol was 94.5 ± 2.47%, followed by ibuprofen 94.03 ± 1.96% and naproxen 81.57 ± 8.74%, respectively. The treatment with the highest removal was the one performed without the presence of gravel substrate. The highest removal efficiency occurred from the third day of exposure for the three compounds, so it was established as the optimum residence time. The model that best explained the adsorption process of the three compounds studied, was the Langmuir isotherm. The observed results demonstrate that L. octovalvis can be used as a native species in artificial wetlands for the efficient removal of pharmaceutical compounds.

Through the use of a macrophyte plant native to the state of Morelos, an artificial wetland was built, which was capable of removing several drugs with tolerance to changes in concentration, which constitutes an economic and sustainable alternative that can be coupled to the treatment of wastewater contaminated with this type of compounds.

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A prominent challenge in understanding neural consequences of substance use involves disentangling predispositional risk factors from resulting consequences of substance use. Existing literature has identified pre-existing brain variations as vulnerability markers for substance use throughout adolescence. As early initiation of use is an important predictor for later substance use problems, we examined whether pre-existing brain variations are associated with early initiation of use. In the Generation R Study, a prospective population-based cohort, brain morphology (gray matter volume, cortical thickness and surface area) was assessed at ages 10 and 14 using neuroimaging. In the second wave, participants reported on alcohol and tobacco use initiation. From a base study population (N = 3019), we examined the longitudinal (N = 2218) and cross-sectional (N = 1817) association between brain morphology of frontolimbic regions of interest known to be associated with substance use risk, and very early (age < 13) alcohol/tobacco use initiation. Additionally, longitudinal and cross-sectional associations were examined with a brain surface-based approach. Models were adjusted for age at neuroimaging, sex and relevant sociodemographic factors. No associations were found between brain morphology (ages 10 and 14) and early alcohol/tobacco use initiation (<13 years). Sex-specific analyses suggested a cross-sectional association between smaller brain volume and early initiated tobacco use in girls. Our findings are important for interpreting studies examining neural consequences of substance use in the general population. Future longitudinal studies are needed to specify whether these findings can be extended to initiation and continuation of alcohol/tobacco use in later stages of adolescence.

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Background: Ulnar nerve compression at the elbow is the second most common compressive neuropathy of the upper extremity. We hypothesize that tension on the ulnar nerve produced by elbow flexion and distraction contributes to this condition. We measured ulnar nerve tension generated during elbow flexion and proportional distraction to evaluate locations of soft tissue constraints to nerve translation. Methods: Eight fresh-frozen upper limb specimens were tested. Each specimen included the proximal humeral shaft to the wrist. The ulnar nerve was dissected proximally and clamped to the humerus 8 â€‹cm proximal to the medial epicondyle. At 8 â€‹cm distal to the medial epicondyle, the ulnar nerve was dissected and clamped distally to a load cell that was mounted on a laboratory stand. A stage on the stand could be translated distally to apply load. Soft tissue was removed distal to the load cell clamp; all soft tissue from the load cell to the proximal humeral clamp was left intact.We measured the tension generated on the nerve throughout the full arc of elbow flexion with additional distal distractions of 0%, 2.5% and 5% of nerve length applied by distal translation of the stage on the lab stand. We then repeated these steps with the nerve unclamped proximally. We then excised 1 â€‹cm of soft tissue distally, clamped the nerve 7 â€‹cm distal to the medial epicondyle, and repeated the measurements. We continued this sequential dissection and testing until the nerve was clamped to the load cell 1 â€‹cm distal to the medial epicondyle. Results: Flexion, distraction, and proximal clamping each increased nerve tension. Tension was greatest at 4, 5, and 6 â€‹cm distal to the medial epicondyle (p â€‹< â€‹0.01). Conclusion: Flexion, distraction, and proximal clamping each increased ulnar nerve tension. The greatest ulnar nerve tension was recorded between 4 and 6 â€‹cm distal to the medial epicondyle.

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Aims: Cardiac magnetic resonance imaging (MRI) is the gold standard in the assessment of left ventricle (LV) mass and wall thickness. In recent years, cardiac computed tomography angiography (CCTA) has gained widespread usage as an imaging modality. Despite this, limited previous investigations have specifically addressed the potential of CCTA as an alternative modality for quantitative LV assessment. The aim of this study was to compare CCTA derived LV mass and wall thickness with cardiac MRI utilizing machine learning algorithms. Methods and results: Fifty-seven participants who underwent both CCTA and cardiac MRI were identified. LV mass and wall thickness was calculated using LV contours which were automatically placed using in-house developed machine learning models. Pearson's correlation coefficients were calculated along with Bland-Altman plots to assess the agreement between the LV mass and wall thickness per region on CCTA and cardiac MRI. Inter-observer correlations were tested using Pearson's correlation coefficient. Average LV mass and wall thickness for CCTA and cardiac MRI were 127 g, 128 g, 7, and 8 mm, respectively. Bland-Altman plots demonstrated mean differences and corresponding 95% limits of agreement of -1.26 (25.06; -27.58) and -0.57 (1.78; -2.92), for LV mass and average LV wall thickness, respectively. Mean differences and corresponding 95% limits of agreement for wall thickness per region were -0.75 (1.34; -2.83), -0.58 (2.14; -3.30), and -0.29 (3.21; -3.79) for the basal, mid, and apical regions, respectively. Inter-observer correlations were excellent. Conclusion: Quantitative assessment of LV mass and wall thickness on CCTA using machine learning algorithms seems feasible and shows good agreement with cardiac MRI.

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Contamination of agricultural soils with heavy metals (HMs) poses a significant environmental threat, especially because industrial discharges often irrigate agricultural lands. A prominent source of HM(s) pollution occurs from tannery effluents containing high concentrations of chromium (Cr) in both Cr3+ and Cr6+ forms along with other toxic materials. Cr is known for its carcinogenic and mutagenic properties in biological systems. Microbe-assisted phytoremediation has emerged as a promising and environmentally friendly approach for detoxifying Cr-contaminated environments. This study aimed to evaluate the performance of citric acid (CA) and a Cr-reducing bacterial strain (Staphylococcus aureus) on the phytoextraction potential of Lemna minor within a Constructed Wetland System treated with tannery wastewater. Various combinations of tannery wastewater (0, 50, and 100 %), CA (0, 5 and 10 mM), and microbial inoculants were applied to the test plants. The mitigative effects of Staphylococcus aureus strain K1 were examined in combination with different concentrations of CA (0, 5, 10 mM). Data on growth and yield attributes highlighted the beneficial effects of bacterial inoculation and CA in ameliorating Cr toxicity in L. minor, as evidenced by increased foliar chlorophyll and carotenoid contents, enhanced antioxidant enzyme activities (SOD, POD, APX, CAT), and improved nutrient uptake. Specifically, CA application resulted in an enhancement of Cr ranging from 12% to 15% and 23%-31% in concentration, and 134%-141% and 322%-337% in Cr accumulation, respectively. When combined with the S. aureus inoculation treatment, CA application (5 and 10 mM) further increased the concentration and accumulation of Cr in L. minor. The enhancement in Cr ranged from 12% to 23% and 27%-41% in concentration, 68%-75%, and 179%-185% in accumulation, respectively. These results demonstrated that L. minor is an effective choice for environmentally friendly Cr remediation due to its continued ability to grow in polluted wastewater. This study suggested that microbial-assisted phytoextraction combined with chelating agents such as CA could be a practical and effective approach for remediating tannery effluents.

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The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.

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OBJECTIVES: Laryngeal Cleft (LC) is an anatomical defect that can cause swallowing difficulties and subsequent recurrent respiratory symptoms. LC can be treated surgically by performing suture repair or by Injection Laryngoplasty (IL). The indications and efficacy of IL are debated among pediatric otolaryngologists. The aim of this survey study was to review the international perspective on IL for LC. METHODS: An online survey was conducted to assess international opinions on the indications and efficacy of IL for LC patients. An online survey was sent to 250 pediatric otolaryngologists worldwide. The survey included questions on the management of LC, the physicians' experience with IL, and their use of IL. RESULTS: Sixty two (25 %) pediatric otolaryngologists, from 47 medical centers, completed the survey. Of the respondents, 38 (62 %) perform IL. The most reported indication was as a diagnostic tool. For the respondents who did not perform IL, the reasons most reported were that the effect is temporary and that there is a need for a second surgery after IL. CONCLUSION: According to this survey, the perspectives on the use of IL for LC differ among pediatric otolaryngologists, and there is variation in peri-and postoperative standard of care. The respondents' opinions on IL were partly dependent on the intended outcome of its use, i.e., as a permanent treatment or for other indications.

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Microplastics are increasingly recognised as posing a significant environmental threat across systems. Their pervasive presence in freshwater poses a serious concern, given the heavy reliance of both humans and biodiversity on healthy, functioning freshwater ecosystems. Acknowledgment of the potential risks led the transboundary Orange-Senqu River Commission (ORASECOM) to include sampling for microlitter (primarily microplastics) in riverine sediment, surface water, and fishes, across Southern Africa as part of the third Joint Basin Survey (JBS3) in 2021. The aim was to establish a first, basin-wide estimate of microlitter contamination across compartments, setting a baseline for further monitoring. The survey showed that the abundance of microlitter in riverine sediment (0 - 4000 particles.kg-1 dry weight (dw)) and riverine water (1.00 ± 0.71 - 69.75 ± 68.55 SD items.L-1) varied considerably between sample sites, with no correlation between the two. The abundance of microlitter in fishes was low (average of 0.7 ± 0.4 items.individual-1). Course resolution analyses suggested that microlitter concentrations in riverine sediment and riverine water at each site did not correlate with land use directly upstream, though variation in microlitter abundance did isolate some hotspots of contamination. Discharge data collected from nine gauging stations near sampling sites confirmed that low flows prevailed in the system during the study, with high flows occurring approximately 5 months prior during the summer months. There is some variation in river flow across the catchment which is a likely driver of microlitter transport. This was evident in the polymer composition for sediment and water samples. Based on the average discharge at each gauging station and microlitter concentrations measured in riverine water, the estimated microlitter load ranged from ∼889 particles.s-1 to ∼17.9 million particles.s-1, with a substantial amount ending likely up in the mudbelt adjacent to the Orange River mouth. This assessment provides a first insight into the characterisation and distribution of microlitter in multiple compartments across the Orange-Senqu River basin. Overall, the findings highlight the need for continued monitoring across compartments at catchment scales to improve our understanding of microplastic pathways into and within riverine systems.

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BACKGROUND AND OBJECTIVE: Systemic corticosteroids have a long history of use in the treatment of autoimmune and inflammatory diseases. Both efficacy and safety show large interindividual variability (IIV), suggesting that corticosteroids may have the potential for individualised dosing strategies to optimise therapy. This systematic review aims to provide an overview of current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in patients with autoimmune and inflammatory diseases. METHODS: A systematic literature search was conducted in PubMed and Embase for PK/PD studies of systemic corticosteroids in autoimmune and inflammatory diseases in humans published until December 2023. Studies were scored from 1 to 5 according to criteria for the levels of evidence, as inspired by the Oxford Centre for Evidence-Based Medicine. RESULTS: Twelve studies (1981-2016) were included. The majority of these studies had a small sample size. The corticosteroids involved were prednisone, prednisolone, methylprednisolone and budesonide. Substantial IIV of corticosteroid PK was described in all studies. Evidence for a relationship between the PK of corticosteroids and efficacy was inconclusive and limited. However, there was some evidence for a relationship between the PK of prednisolone and the severity of Cushingoid features. CONCLUSION: There is insufficient evidence to draw firm conclusions on the potential associations between PK and clinical outcome of systemic corticosteroid treatment in autoimmune and inflammatory diseases. This is remarkable given the many decades that steroid drugs have been used in clinical care. Prospective research is recommended with robust and well-defined cohorts to fully quantify the PK/PD associations of corticosteroids.

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This study aimed to estimate the hepatic and immune ameliorating potential of extracted bovine lactoferrin (LF), Selenium nanoparticles (SeNPs) or their combination (LF/SeNPs) against bleomycin (BLM) induced hepatic injury. Fifty adult male rats (160-200 g) were equally divided into five groups: (1) the saline control group, (2) BLM-injected (15 mg/kg twice a week, ip), and (3-5) groups treated orally with LF (200 mg/kg/day), SeNPs (0.0486 mg/kg/day) or LF/SeNPs combination (200.0486 mg/kg/day) for 6 weeks post BLM-intoxication. Blood and liver samples were subjected to biochemical, histopathological, and immunohistochemical analyses. The results revealed that BLM caused a significant increase in hepatic lipid peroxidation and nitric oxide, as well as serum markers of liver functions (AST, ALT and GGT activities), and levels of GM-CSF, CD4, TNF-α, IL-1ß, TGF-ß1, fibronectin, triglycerides, cholesterol and LDL-C. Additionally, hepatic glutathione, Na+/K+-ATPase, and glutathione peroxidase, as well as serum HDL-C, total protein and albumin levels were significantly reduced. Moreover, BLM injection resulted in marked histopathological alterations and severe expression of caspase 3. Post-treatment of BLM-intoxicated rats with LF, SeNPs or LF/SeNPs combination obviously improved the BLM-induced hepatic damages; this was achieved from the marked modulations in the mentioned parameters, besides improving the histopathological hepatic architecture. It is worth mentioning that LF/SeNPs exerted the greatest potency. In conclusion, the obtained results demonstrated that LF, SeNPs and LF/SeNPs succeeded in attenuating the BLM-induced hepatic dysfunction. Therefore, these supplements might be used to protect against drug-associated side effects.

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BACKGROUND: Data on the clinicopathological characteristics of mucinous gastric cancer (muc-GC) are limited. This study compares the clinical outcome and response to chemotherapy between patients with resectable muc-GC, intestinal (int-GC) and diffuse (dif-GC) gastric cancer. METHODS: Patients from the D1/D2 study or the CRITICS trial were included in exploratory surgery-alone (SAtest) or chemotherapy test (CTtest) cohorts. Real-world data from the Netherlands Cancer Registry on patients treated between with surgery-alone (SAvalidation), and receiving preoperative chemotherapy with or without postoperative treatment (CTvalidation) were used for validation. Histopathological subtypes were extracted from pathology reports filed in the Dutch Pathology Registry and correlated with tumor regression grade (TRG) and relative survival (RS). RESULTS: In SAtest (n = 549) and SAvalidation (n = 8062) cohorts, muc-GC patients had a five-year RS of 39% and 31%, similar to or slightly better than dif-GC (43% and 29%, p = .52 and p = .011), but worse than int-GC (55% and 42%, p = .11 and p < .001). In CTtest (n = 651) and CTvalidation (n = 2889) cohorts, muc-GC showed favorable TRG (38% and 44% (near-)complete response) compared to int-GC (26% and 35%) and dif-GC (10% and 28%, p < .001 and p = .005). The 5-year RS in CTtest and CTvalidation cohorts for muc-GC (53% and 48%) and int-GC (58% and 59%) was significantly better compared to dif-GC (35% and 38%, p = .004 and p < .001). CONCLUSION: Recognizing and incorporating muc-GC into treatment decision-making of resectable GC can lead to more personalized and effective approaches, given its favorable response to preoperative chemotherapy in relation to int-GC and dif-GC and its favorable prognostic outcomes in relation to dif-GC.

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Multiple genotypes of highly pathogenic avian influenza (HPAI) H5 clade 2.3.4.4b viruses have caused epizootics in wild birds and poultry. The HPAI H5N1 genotype C virus caused a modest epizootic, whereas the occurrence of the HPAI H5N1 genotype AB virus in 2021 resulted in the largest avian influenza epizootic in Europe to date. Here we studied the pathogenicity of two HPAI H5N1 viruses by experimentally infecting chickens, Pekin ducks, Eurasian wigeons and Barnacle geese. Our study demonstrates that pathogenicity of the H5N1-2021-AB virus is lower in Pekin ducks, Eurasian wigeons and Barnacle geese compared to the H5N1-2020-C virus, whereas virus shedding was high for both viruses. After inoculation with H5N1-2021-C viral antigen expression was higher in the brain of Pekin ducks, Eurasian wigeons and Barnacle geese, which caused higher mortality compared to inoculation with H5N1-2021-AB virus. Subclinical infections occurred in Pekin ducks and Eurasian wigeons and mortality was reduced in Barnacle geese after inoculation with H5N1-2021-AB virus while H5N1-2020-C virus caused high morbidity and mortality in these species. This H5N1-2021-AB virus trait may have contributed to efficient spread of the virus in wild bird populations. Therefore, high mortality, virus shedding and long-lasting viral antigen expression found in Barnacle geese may have increased the risk for introduction into poultry.

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It is generally assumed that contact angle hysteresis of superhydrophobic surfaces scales with liquid-solid contact fraction, however, its experimental verification has been problematic due to the limited accuracy of contact angle and sliding angle goniometry. Advances in cantilever-based friction probes enable accurate droplet friction measurements down to the nanonewton regime, thus suiting much better for characterizing the wetting of superhydrophobic surfaces than contact angle hysteresis measurements. This work quantifies the relationship between droplet friction and liquid-solid contact fraction, through theory and experimental validation. Well-defined micropillar and microcone structures are used as model surfaces to provide a wide range of different liquid-solid contact fractions. Micropillars are known to be able to hold the water on top of them, and a theoretical analysis together with confocal laser scanning microscopy shows that despite the spiky nature of the microcones droplets do not sink into the conical structure either, rendering a diminishingly small liquid-solid contact fraction. Droplet friction characterization with a micropipette force sensor technique reveals a strong dependence of the droplet friction on the contact fraction, and the dependency is described with a simple physical equation, despite the nearly three-orders-of-magnitude difference in liquid-solid contact fraction between the sparsest cone surface and the densest pillar surface.

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Background Thyroid-stimulating hormone (TSH) and subsequent free thyroxine (FT4) concentrations outside the reference interval (RI) are used to diagnose thyroid diseases. Most laboratories do not provide age-specific RIs for TSH and FT4 beyond childhood, although TSH concentrations vary with age. Therefore, we aimed to establish TSH and FT4 age-specific RIs throughout life and aimed to determine whether using these RIs would result in reclassification of thyroid disease diagnoses in adults. Methods This multicenter retrospective cross-sectional study used big data to determine indirect RIs for TSH and FT4. These RIs were determined by TMC and refineR-analysis, respectively, using four different immunoassay platforms (Roche, Abbott, Siemens, Beckman Coulter). Retrospective data (2008-2022) from 13 Dutch laboratories for general practitioners and local hospitals were used. RIs were evaluated per manufacturer. Age groups were established from 2-20 years by 2-year categories and decade categories between 20 and 100 years. Results We included totally 7.6 million TSH and 2.2 million FT4 requests. TSH upper reference limits (URLs) and FT4 lower reference limits (LRLs) were higher in early childhood and decreased towards adulthood. In adulthood, TSH URLs increased from 60 years in men, and from 50 years in women, while FT4 URLs increased from 70 years onwards. Using adult age-specific RIs resulted in a decrease in diagnoses of subclinical and overt hypothyroidism in women above 50 and men above 60 years in our Roche dataset. Conclusion This study stressed the known importance of using age-specific RIs for TSH and FT4 in children. This study also showed the clinical relevance of using age-specific RIs for TSH in adulthood to reduce diagnoses of subclinical hypothyroidism in older persons. Therefore, implementation of adult TSH age-specific RIs should be strongly considered. Data is less uniform regarding FT4 age-specific RIs and more research should be performed before implementing these in clinical practice.

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PURPOSE: In this study, we aimed to explore if the combination of tumor infiltrating lymphocytes (TILs) and change in tumor load on dynamic contrast-enhanced magnetic resonance imaging leads to better assessment of response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, compared to either alone. METHODS: In 190 NAC treated patients, MRI scans were performed before and at the end of treatment. The percentage of stromal TILs (%TILs) was assessed in pre-NAC biopsies according to established criteria. Prediction models were developed with linear regression by least absolute shrinkage and selection operator and cross validation (CV), with residual cancer burden as the dependent variable. Discrimination for pathological complete response (pCR) was evaluated using area under the receiver operating characteristic curves (AUC). We used Cox regression analysis for exploring the association between %TILs and recurrence-free survival (RFS). RESULTS: Fifty-one patients reached pCR. In all patients, the %TILs model and change in MRI tumor load model had an estimated CV AUC of 0.69 (95% confidence interval (CI) 0.53-0.78) and 0.69 (95% CI 0.61-0.79), respectively, whereas a model combining the variables resulted in an estimated CV AUC of 0.75 (95% CI 0.66-0.83). In the group with tumors that were ER positive and HER2 negative (ER+/HER2-) and in the group with tumors that were either triple negative or HER2 positive (TN&HER2+) separately, the combined model reached an estimated CV AUC of 0.72 (95% CI 0.60-0.88) and 0.70(95% CI 0.59-0.82), respectively. A significant association was observed between pre-treatment %TILS and RFS (hazard ratio (HR) 0.72 (95% CI 0.53-0.98), for every standard deviation increase in %TILS, p = 0.038). CONCLUSION: The combination of TILs and MRI is informative of response to NAC in patients with both ER+/HER2- and TN&HER2+ tumors.