AKT and EZH2 inhibitors kill TNBCs by hijacking mechanisms of involution.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and has the highest rate of recurrence1. The predominant standard of care for advanced TNBC is systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there is an urgent need to develop more effective treatments. Components of the PI3K pathway represent plausible therapeutic targets; more than 70% of TNBCs have alterations in PIK3CA, AKT1 or PTEN3-6. However, in contrast to hormone-receptor-positive tumours, it is still unclear whether or how triple-negative disease will respond to PI3K pathway inhibitors7. Here we describe a promising AKT-inhibitor-based therapeutic combination for TNBC. Specifically, we show that AKT inhibitors synergize with agents that suppress the histone methyltransferase EZH2 and promote robust tumour regression in multiple TNBC models in vivo. AKT and EZH2 inhibitors exert these effects by first cooperatively driving basal-like TNBC cells into a more differentiated, luminal-like state, which cannot be effectively induced by either agent alone. Once TNBCs are differentiated, these agents kill them by hijacking signals that normally drive mammary gland involution. Using a machine learning approach, we developed a classifier that can be used to predict sensitivity. Together, these findings identify a promising therapeutic strategy for this highly aggressive tumour type and illustrate how deregulated epigenetic enzymes can insulate tumours from oncogenic vulnerabilities. These studies also reveal how developmental tissue-specific cell death pathways may be co-opted for therapeutic benefit.

Trends in prevalence of adverse childhood experiences by sociodemographic factors in the United States: Behavioral Risk Factor Surveillance System 2009-2022.

BACKGROUND: Limited data exists on trends in prevalence of adverse childhood experiences (ACE) at the national level and sociodemographic correlates of having ACEs. This study examined trends in ACE prevalence and sociodemographic correlates in US adults over 14 years using nationally representative data. METHODS: Data on 447,162 adults from the Behavioral Risk Factor Surveillance System (BRFSS) across four timepoints (2009-2010; 2011-2012; 2019-2020; 2021-2022) was analyzed and weighted for population estimates. The primary outcome was ACEs with 3 groups used (0 vs. 1 + ACEs; <4 vs. 4 + ACEs; 0 vs. 1 vs. 2 vs. 3 vs. 4 + ACEs). Sociodemographic factors included age, sex, race/ethnicity, employment, education, marital status, income and insurance status. Prevalence trends were examined by estimating prevalence of ACE groupings (0/1+; <4/4+; 0,1,2,3,4+) across the four timepoints and trend analysis was performed to determine if the differences over time were statistically significant. Unadjusted and adjusted prevalence ratios were estimated using log-binomial regression models with ACE groupings as the outcome and timepoints as the primary independent variable with sociodemographic factors as covariates. RESULTS: Across the four time points, prevalence of ACEs was higher across groupings of ACEs by time. For ACEs 1+, prevalence was 62.2% (2009-2010); 62.2% (2011-2012); 64.5% (2019-2020); and 67.2% (2021-2022). For ACEs 4+, prevalence was 17.4% (2009-2010); 18.1% (2011-2012); 20.4% (2019-2020); and 22.6% (2021-2022). Prevalence of ACE 1 + was higher for older adults, Non-Hispanic Black adults, Non-Hispanic Other adults, and those with higher education. Prevalence of 4 + ACEs was higher for females, and lower for those with higher education and those with higher annual incomes. CONCLUSION: This study shows an increased prevalence of having ACEs over a 14-year period and identified independent sociodemographic correlates of having ACEs in a nationally representative study. Targeted interventions are needed to reduce burden of ACEs using population-based approaches.

Dimensionless parameter predicts bacterial prodrug success.

Understanding mechanisms of antibiotic failure is foundational to combating the growing threat of multidrug-resistant bacteria. Prodrugs-which are converted into a pharmacologically active compound after administration-represent a growing class of therapeutics for treating bacterial infections but are understudied in the context of antibiotic failure. We hypothesize that strategies that rely on pathogen-specific pathways for prodrug conversion are susceptible to competing rates of prodrug activation and bacterial replication, which could lead to treatment escape and failure. Here, we construct a mathematical model of prodrug kinetics to predict rate-dependent conditions under which bacteria escape prodrug treatment. From this model, we derive a dimensionless parameter we call the Bacterial Advantage Heuristic (BAH) that predicts the transition between prodrug escape and successful treatment across a range of time scales (1-104 h), bacterial carrying capacities (5 × 104 -105 CFU/µl), and Michaelis constants (KM = 0.747-7.47 mM). To verify these predictions in vitro, we use two models of bacteria-prodrug competition: (i) an antimicrobial peptide hairpin that is enzymatically activated by bacterial surface proteases and (ii) a thiomaltose-conjugated trimethoprim that is internalized by bacterial maltodextrin transporters and hydrolyzed by free thiols. We observe that prodrug failure occurs at BAH values above the same critical threshold predicted by the model. Furthermore, we demonstrate two examples of how failing prodrugs can be rescued by decreasing the BAH below the critical threshold via (i) substrate design and (ii) nutrient control. We envision such dimensionless parameters serving as supportive pharmacokinetic quantities that guide the design and administration of prodrug therapeutics.

The association between dairy products consumption and prostate cancer risk: a systematic review and meta-analysis.

In this study, we conducted a meta-analysis to estimate the relationship between the consumption of dairy products and the risk of prostate cancer. We searched PubMed, Embase and Cochrane databases for relevant articles and identified a total of thirty-three cohort studies between 1989 and 2020. The qualities of included studies were assessed using Newcastle-Ottawa scale. Pooled adjusted relative risks (RR) with 95 % CI were calculated. We performed subgroup analyses stratified by dairy type, prostate cancer type, follow-up years, treatment era, collection times, adjustment for confounders and geographic location. In the subgroup analysis stratified by prostate cancer type, the pooled RR were 0·98 (95 % CI 0·94, 1·03) in the advanced group, 1·10 (95 % CI 0·98, 1·24) in the non-advanced group and 0·92 (95 % CI 0·84, 1·00) in the fatal group. In the dose-response analysis, a positive association for the risk of prostate cancer was observed for total dairy products 400 g/d (RR: 1·02; 95 % CI 1·00, 1·03), total milk 200 g/d (RR: 1·02; 95 % CI 1·01, 1·03), cheese 40 g/d (RR: 1·01; 95 % CI 1·00, 1·03) and butter 50 g/d (RR: 1·03; 95 % CI 1·01, 1·05). A decreased risk was observed for the intake of whole milk 100 g/d (RR: 0·97; 95 % CI 0·96, 0·99). Our meta-analysis suggests that high intakes of dairy products may be associated with an increased risk of prostate cancer; however, since many of the studies were affected by prostate-specific antigen (PSA) screening bias, additional studies with an adjustment of PSA screening are needed.

Comparisons of objective and subjective refraction with and without cycloplegia using binocular wavefront optometer with autorefraction and retinoscopy in school-age children.

PURPOSE: To compare school-age children's objective and subjective refraction using a binocular wavefront optometer (BWFOM) with autorefraction and retinoscopy before and after cycloplegia. METHODS: Eighty-six eyes from 86 children (6-15 years old) were enrolled in this cross-sectional study. BWFOM objective and subjective refractions were compared with autorefraction and retinoscopy under cycloplegia. BWFOM refraction was evaluated before and after cycloplegia. Measurements were compared using a paired t-test; agreement was assessed using Bland-Altman plots. RESULTS: Under cycloplegia, the sphere, spherical equivalence, and J45 were significantly more negative on BWFOM objective refraction than autorefraction (- 1.39 ± 2.20 D vs. - 1.28 ± 2.23 D, P = 0.003; - 1.84 ± 2.38 D vs. - 1.72 ± 2.43 D, P = 0.001; - 0.02 ± 0.17 D vs. 0.03 ± 0.21 D, P = 0.004). The subjective sphere of BWFOM was less myopic, and the cylinder and the J45 were more negative than those with retinoscopy (- 1.17 ± 2.09 D vs. - 1.25 ± 2.20 D, P = 0.02; - 0.91 ± 0.92 D vs. - 0.76 ± 0.92 D, P < 0.001; - 0.01 ± 0.15 D vs. 0.03 ± 0.21 D, P = 0.028). For both BWFOM objective and subjective refraction, sphere and spherical equivalence with noncycloplegia were more myopic than those with cycloplegia (objective: - 1.76 ± 2.10 D vs. - 1.39 ± 2.20 D, - 2.21 ± 2.30 D vs. - 1.84 ± 2.38 D, P < 0.001; subjective: - 1.57 ± 1.92 D vs. - 1.17 ± 2.09 D, - 2.01 ± 2.13 D vs. - 1.62 ± 2.27 D, P < 0.001). Bland-Altman plots showed good agreement in spherical equivalence between BWFOM objective refraction and autorefraction (mean difference = 0.12 D, 95% confidence interval [CI] - 0.52 to 0.76), subjective refraction with retinoscopy (mean difference = - 0.01 D, 95% CI - 0.65 to 0.64), and BWFOM refractions with or without cycloplegia (objective: mean difference = - 0.37 D, 95% CI - 1.31 to 0.57; subjective: mean difference = - 0.39 D, 95% CI - 1.30 to 0.51). The time cost by BWFOM was significantly less than the total time of autorefraction and retinoscopy (264.88 ± 90.67 s vs. 315.89 ± 95.31 s, P < 0.001). CONCLUSION: BWFOM is a new device that realizes both objective and subjective refraction. For children's refractive errors, it is more convenient and quicker to obtain the proper prescription at a 0.05-D interval, and it is more accurate than autorefraction and retinoscopy under cycloplegia.

Dynamic range enhancement of self-referenced spectral interferometry with extended time excursion method by the cascaded Kerr lens process.

Self-referenced spectral interferometry with extended time excursion (SRSI-ETE) is a powerful method for single-shot characterization of the temporal contrast of a high peak power laser, which has high temporal resolution but a low dynamic range. Here, a temporal contrast reduction method is proposed that uses the cascaded Kerr lens process in two thin glass plates. Combined with the SRSI-ETE method, the measurement dynamic range of the method is increased about two orders of magnitude while having a 20 fs temporal resolution and a 40 ps time window in single shot.

Use of different ligand modification liposomes to evaluate the anti-liver tumor activity of cantharidin.

In this study, cantharidin(CTD), a bioactive terpenoid in traditional Chinese medicine cantharidin, was selected as a model component to construct novel nano liposome delivery systems for hepatocellular carcinoma therapy. Previous studies have shown that although cantharidin has definite curative effects on primary liver cancer, it is associated with numerous toxic and side effects. Therefore, based on the glycyrrhetinic acid (GA) binding site and the asialoglycoprotein receptor (ASGPR) on the hepatocyte membrane, the surface of CTD liposomes was modified with stearyl alcohol galactoside (SA-Gal) or/and the newly synthesized 3-succinic-30-stearyl deoxyglycyrrhetinic acid (11-DGA-Suc) ligands, and the physicochemical properties, pharmacokinetics, in vivo and in vitro anti-liver tumor activity and its mechanism of modified liposomes were investigated. Compared to CTD-lip, SA-Gal-CTD-lip, and 11-DGA-Suc + SA-Gal-CTD-lip, 11-DGA-Suc-CTD-lip showed stronger cytotoxicity and increased inhibition of HepG2 cell migration had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells was arrested mainly at G0/G1phase and G2/M phase. The results of in vivo pharmacokinetic experiments revealed that the distribution of modified liposomes in the liver was significantly increased compared with that of unmodified liposome. In vivo tumor inhibition experiment showed that 11-DGA-Suc-CTD-lip had excellent tumor inhibition, and the tumor inhibition rates was 80.96%. The 11-DGA-Suc-CTD-lip group also displayed the strongest proliferation inhibition with the lowest proliferation index of 7% in PCNA assay and the highest apoptotic index of 49% in TUNEL assay. Taken together, our findings provide a promising solution for improving the targeting of nano liposomes and further demonstrates the encouraging potential of poor solubility and high toxicity drugs applicable to tumor therapy.

3D-printed facet-attached optical elements for beam shaping in optical phased arrays.

We demonstrate an optical phased-array equipped with a 3D-printed facet-attached element for shaping and deflection of the emitted beam. The beam shaper combines freeform refractive surfaces with total-internal-reflection mirrors and is in-situ printed to edge-emitting waveguide facets using high-resolution multi-photon lithography, thereby ensuring precise alignment with respect to on-chip waveguide structures. In a proof-of-concept experiment, we achieve a grating-lobe free steering range of ±30∘ and a full-width-half-maximum beam divergence of approximately 2∘. The concept opens an attractive alternative to currently used grating structures and is applicable to a wide range of integration platforms.

3D-printed facet-attached optical elements for connecting VCSEL and photodiodes to fiber arrays and multi-core fibers.

Multicore optical fibers and ribbons based on fiber arrays allow for massively parallel transmission of signals via spatially separated channels, thereby offering attractive bandwidth scaling with linearly increasing technical effort. However, low-loss coupling of light between fiber arrays or multicore fibers and standard linear arrays of vertical-cavity surface-emitting lasers (VCSEL) or photodiodes (PD) still represents a challenge. In this paper, we demonstrate that 3D-printed facet-attached microlenses (FaML) offer an attractive path for connecting multimode fiber arrays as well as individual cores of multimode multicore fibers to standard arrays of VCSEL or PD. The freeform coupling elements are printed in situ with high precision on the device and fiber facets by high-resolution multi-photon lithography. We demonstrate coupling losses down to 0.35 dB along with lateral 1 dB alignment tolerances in excess of 10 µm, allowing to leverage fast passive assembly techniques that rely on industry-standard machine vision. To the best of our knowledge, our experiments represent the first demonstration of a coupling interface that connects individual cores of a multicore fiber to VCSEL or PD arranged in a standard linear array without the need for additional fiber-based or waveguide-based fan-out structures. Using this approach, we build a 3 × 25 Gbit/s transceiver assembly which fits into a small form-factor pluggable module and which fulfills many performance metrics specified in the IEEE 802.3 standard.

FOXM1-induced TYMS upregulation promotes the progression of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the major causes of cancer-related death. Thymidylate synthase (TYMS) catalyzes the methylation of deoxy guanosine to deoxy thymidylate, which is a crucial gene for DNA repair and replication. Thus, TYMS was reported to be closely associated with developing a variety of tumors, but it has been poorly studied in HCC. MATERIALS AND METHODS: We used the cell counting kit-8 (CCK-8), BrdU, and CFSE assay to measure cell proliferation. The flow cytometry assay and the TUNEL assay were used for assessing cell apoptosis. The flow cytometry assay was used to analyze the cell cycle. The Transwell invasion assay and the wound healing assay were conducted to determine the invasive ability of the cells. RT-qPCR and Western blot analyses were performed to evaluate the mRNA and protein expression levels of specific genes, respectively. RESULTS: TYMS was found to be upregulated in both HCC cells and patient samples. High expression of TYMS was associated with an unfavorable prognosis in HCC patients based on the TCGA-LIHC dataset. Cell proliferation, apoptosis, and invasion assays revealed that TYMS promoted the proliferation and invasion of HCC cells as well as inhibited apoptosis. In addition, TYMS is a downstream target of FOXM1. TYMS knockdown reversed the 5-FU resistance caused by FOXM1 overexpression and re-sensitized HCC cells to 5-FU treatment. CONCLUSION: This study suggested that TYMS serves as an oncogene in HCC, and targeting the FOXM1-TYMS axis may help improve the survival of HCC patients as well as provide new insights for treating advanced HCC patients.

Epidemiology of Birth Defects in Eastern China and the Associated Risk Factors.

BACKGROUND This study aimed to survey the overall situation of birth defects (BDs) among citizens of Hangzhou, China, and the risk factors of different BD types. MATERIAL AND METHODS We collected the data of 4349 perinatal infants with BDs in Hangzhou. The potentially associated risk factors of BDs were recorded and logistic regression analysis was used to predict the high incidence of BDs. RESULTS Among all perinatal infants with BDs, there were 4105 (94.3%) single births, 225 (5.2%) twin births, and 10 (0.2%) multiple births. In clinical outcomes, there were 2477 (57.0%) live births, 1806 (41.5%) dead fetuses, and 11 (0.3%) stillbirths. Down syndrome ranked first, accounting for 30.7% of the total births, followed by cleft lip and polydactyly. Low family income, nulliparity, high parity, high education level, and taking contraceptives in early pregnancy were found to be risk factors of Down syndrome. Low parity, low education level, and pesticide exposure were found to be risk factors of cleft lip. For polydactyly, young age of the mother and a parity above 0 were identified as risk factors. CONCLUSIONS Different risks factors can influence BD development and potentially help to predict specific BD types, such as demographic features and harmful exposure in early pregnancy.

Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing.

Tumor metastasis remains the major cause of cancer-related death, but its molecular basis is still not well understood. Here we uncovered a splicing-mediated pathway that is essential for breast cancer metastasis. We show that the RNA-binding protein heterogeneous nuclear ribonucleoprotein M (hnRNPM) promotes breast cancer metastasis by activating the switch of alternative splicing that occurs during epithelial-mesenchymal transition (EMT). Genome-wide deep sequencing analysis suggests that hnRNPM potentiates TGFß signaling and identifies CD44 as a key downstream target of hnRNPM. hnRNPM ablation prevents TGFß-induced EMT and inhibits breast cancer metastasis in mice, whereas enforced expression of the specific CD44 standard (CD44s) splice isoform overrides the loss of hnRNPM and permits EMT and metastasis. Mechanistically, we demonstrate that the ubiquitously expressed hnRNPM acts in a mesenchymal-specific manner to precisely control CD44 splice isoform switching during EMT. This restricted cell-type activity of hnRNPM is achieved by competition with ESRP1, an epithelial splicing regulator that binds to the same cis-regulatory RNA elements as hnRNPM and is repressed during EMT. Importantly, hnRNPM is associated with aggressive breast cancer and correlates with increased CD44s in patient specimens. These findings demonstrate a novel molecular mechanism through which tumor metastasis is endowed by the hnRNPM-mediated splicing program.

Development of Glycyrrhetinic Acid and Folate Modified Cantharidin Loaded Solid Lipid Nanoparticles for Targeting Hepatocellular Carcinoma.

Cantharidin (CTD) is the major component of anticancer drugs obtained from Mylabris Cichorii and has a good inhibitory effect on several cancers, including hepatocellular carcinoma (HCC) and breast cancer. However, due to its toxicity, oral administration can cause various adverse reactions, limiting its clinical application. The aim of this work was to design glycyrrhetinic acid (GA)- and/or folate (FA)-modified solid lipid nanoparticles (SLNs) for the encapsulation of CTD to target HCC. Four CTD-loaded SLNs (cantharidin solid lipid nanoparticles (CSLNs), glycyrrhetinic acid-modified cantharidin solid lipid nanoparticles (GA-CSLNs), folate-modified cantharidin solid lipid nanoparticles (FA-CSLNs), and glycyrrhetinic acid and folate-modified cantharidin solid lipid nanoparticles (GA-FA-CSLNs)) were prepared by the emulsion ultrasonic dispersion method, and their physicochemical parameters were determined (particle size and distribution, morphology, zeta-potential, entrapment efficiency, drug loading, and hemolysis). Additionally, the antitumor activities of the four SLNs were evaluated comprehensively by tests for cytotoxicity, cell migration, cell cycle, apoptosis, cellular uptake, competition suppression assay, and in vivo tumor suppression assay. Four SLNs showed spherical shapes and mean diameters in the range of 75-110 nm with size dispersion (PDI) within the range of 0.19-0.50 and zeta-potential approximately -10 mV. The entrapment efficiency of CTD in SLNs was higher than 95% for all tested formulations, and no hemolysis was observed. Compared to GA-CSLNs or CSLNs, GA-FA-CSLNs and FA-CSLNs showed stronger cytotoxicity on hepatocellular carcinoma cells (HepG2), and the cytotoxicity of GA-FA-CSLNs on hepatocyte cells (L-02) was remarkably reduced compared with other formulations. GA-FA-CSLNs and FA-CSLNs also increased the inhibition of HepG2 cell migration, and FA-CSLNs had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells were arrested mainly in the S phase and G2/M phase. Analysis of competition inhibition experiments showed that GA and FA ligands had targeted effects on HepG2 cells. The in vivo tumor inhibition experiment showed that GA-FA-CSLNs and FA-CSLNs had excellent tumor inhibition ability-their tumor inhibition rates were 96.46% and 89.92%, respectively. Our results indicate that GA-FA-CSLNs and FA-CSLNs have a promising future in the therapeutic intervention of HCC.

Superconducting nanowire single-photon detector with 3D-printed free-form microlenses.

We present an approach to increase the effective light-receiving area of superconducting nanowire single-photon detectors (SNSPD) by free-form microlenses. These lenses are printed in situ on top of the sensitive detector areas using high-resolution multi-photon lithography. We demonstrate a detector based on niobium-nitride (NbN) nanowires with a 4.5 µm × 4.5 µm sensitive area, supplemented with a lens of 60-µm-diameter. For a plane-wave-like free-space illumination at a wavelength of 1550 nm, the lensed sensor has a 100-fold increased effective collection area, which leads to a strongly enhanced system detection efficiency without the need for long nanowires. Our approach can be readily applied to a wide range of sensor types. It effectively overcomes the inherent design conflict between high count rate, high timing accuracy, and high fabrication yield on the one hand and high collection efficiency through a large effective detection area on the other hand.

4-Phenylbutyric acid protects islet ß cell against cellular damage induced by glucocorticoids.

This study, using the MIN6 cell line, examines the effect of glucocorticoids (GCs) on the expression and protein levels of endoplasmic reticulum stress (ERS) related genes. Furthermore, we evaluated the protective role of 4-phenylbutyric acid (4-PBA) on the aforesaid GCs induced changes. Pancreatic islet MIN6 cells were treated with dexamethasone (DEX) at distinct concentrations (0.1 µmol/L and 0.5 µmol/L) for different periods (1 h, 4 h, 12 h, and 24 h). The mRNA and protein levels of ERS related genes were measured using real-time qPCR (qRT-PCR) and western blotting. Similar evaluations were also carried out for the cells treated with 4-PBA combined with DEX. Upon DEX intervention which induces the unfolded protein response (UPR), the expression levels of BIP, ATF6, IRE1, and PERK increased in the MIN6 cells, both in concentration and time-dependent manner. Similarly, ERS associated gene CHOP, which is involved in the apoptotic pathway, also showed increased levels both in concentration and time-dependent manner. However, treatment with 4-PBA decreased the expression levels of ERS related proteins. Quantitative analysis found that all these results were statistically significant (P < 0.05). GCs markedly activates the ERS in the MIN6 cell line in vitro, however, this effect can be significantly alleviated upon treatment with 4-PBA.

3D-M3: high-spatial-resolution spectroscopy with extreme AO and 3D-printed micro-lenslets.

By combining integral field spectroscopy with extreme adaptive optics, we are now able to resolve objects close to the diffraction limit of large telescopes, exploring new science cases. We introduce an integral field unit designed to couple light with a minimal plate scale from the SCExAO facility at NIR wavelengths to a single-mode spectrograph. The integral field unit has a 3D-printed micro-lens array on top of a custom single-mode multi-core fiber, to optimize the coupling of light into the fiber cores. We demonstrate the potential of the instrument via initial results from the first on-sky runs at the 8.2 m Subaru Telescope with a spectrograph using off-the-shelf optics, allowing for rapid development with low cost.

Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT.

The epithelial-mesenchymal transition (EMT) is a fundamental developmental process that is abnormally activated in cancer metastasis. Dynamic changes in alternative splicing occur during EMT. ESRP1 and hnRNPM are splicing regulators that promote an epithelial splicing program and a mesenchymal splicing program, respectively. The functional relationships between these splicing factors in the genome scale remain elusive. Comparing alternative splicing targets of hnRNPM and ESRP1 revealed that they coregulate a set of cassette exon events, with the majority showing discordant splicing regulation. Discordant splicing events regulated by hnRNPM show a positive correlation with splicing during EMT; however, concordant events do not, indicating the role of hnRNPM in regulating alternative splicing during EMT is more complex than previously understood. Motif enrichment analysis near hnRNPM-ESRP1 coregulated exons identifies guanine-uridine rich motifs downstream from hnRNPM-repressed and ESRP1-enhanced exons, supporting a general model of competitive binding to these cis-elements to antagonize alternative splicing. The set of coregulated exons are enriched in genes associated with cell migration and cytoskeletal reorganization, which are pathways associated with EMT. Splicing levels of coregulated exons are associated with breast cancer patient survival and correlate with gene sets involved in EMT and breast cancer subtyping. This study identifies complex modes of interaction between hnRNPM and ESRP1 in regulation of splicing in disease-relevant contexts.

3D-printed optical probes for wafer-level testing of photonic integrated circuits.

Wafer-level probing of photonic integrated circuits is key to reliable process control and efficient performance assessment in advanced production workflows. In recent years, optical probing of surface-coupled devices such as vertical-cavity lasers, top-illuminated photodiodes, or silicon photonic circuits with surface-emitting grating couplers has seen great progress. In contrast to that, wafer-level probing of edge-emitting devices with hard-to-access vertical facets at the sidewalls of deep-etched dicing trenches still represents a major challenge. In this paper, we address this challenge by introducing a novel concept of optical probes based on 3D-printed freeform coupling elements that fit into deep-etched dicing trenches on the wafer surface. Exploiting the design freedom and the precision of two-photon laser lithography, the coupling elements can be adapted to a wide variety of mode-field sizes. We experimentally demonstrate the viability of the approach by coupling light to edge-emitting waveguides on different integration platforms such as silicon photonics (SiP), silicon nitride (TriPleX), and indium phosphide (InP). Achieving losses down to 1.9 dB per coupling interface, we believe that 3D-printed coupling elements represent a key step towards highly reproducible wafer-level testing of edge-coupled photonic integrated circuits.

Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A.

CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.

The CD44s splice isoform is a central mediator for invadopodia activity.

The ability for tumor cells to spread and metastasize to distant organs requires proteolytic degradation of extracellular matrix (ECM). This activity is mediated by invadopodia, actin-rich membrane protrusions that are enriched for proteases. However, the mechanisms underlying invadopodia activity are not fully understood. Here, we report that a specific CD44 splice isoform, CD44s, is an integral component in invadopodia. We show that CD44s, but not another splice isoform CD44v, is localized in invadopodia. Small hairpin (sh)RNA-mediated depletion of CD44s abolishes invadopodia activity, prevents matrix degradation and decreases tumor cell invasiveness. Our results suggest that CD44s promotes cortactin phosphorylation and recruits MT1-MMP (also known as MMP14) to sites of matrix degradation, which are important activities for invadopodia function. Importantly, we show that depletion of CD44s inhibits breast cancer cell metastasis to the lung in animals. These findings suggest a crucial mechanism underlying the role of the CD44s splice isoform in breast cancer metastasis.