Acetylation-dependent regulation of Skp2 function.

Aberrant Skp2 signaling has been implicated as a driving event in tumorigenesis. Although the underlying molecular mechanisms remain elusive, cytoplasmic Skp2 correlates with more aggressive forms of breast and prostate cancers. Here, we report that Skp2 is acetylated by p300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase. Inactivation of SIRT3 leads to elevated Skp2 acetylation, which leads to increased Skp2 stability through impairment of the Cdh1-mediated proteolysis pathway. As a result, Skp2 oncogenic function is increased, whereby cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo. Moreover, acetylation of Skp2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic Skp2 enhances cellular migration through ubiquitination and destruction of E-cadherin. Thus, our study identifies an acetylation-dependent regulatory mechanism governing Skp2 oncogenic function and provides insight into how cytoplasmic Skp2 controls cellular migration.

Ultra-low-complexity weight-sharing trigonometric nonlinear equalizer for beyond net-200-Gb/s/λ short-reach optical interconnects.

An ultra-low-complexity third-order weight-sharing trigonometric nonlinear equalizer (WS-TNLE) is proposed to eliminate nonlinear signal distortions in short-reach optical interconnects exceeding net 200 Gb/s/λ. By replacing the second- and third-order nonlinear terms in a third-order weight-sharing diagonally pruned Volterra nonlinear equalizer (WS-DP-VNLE) with cosine and sine terms, respectively, the required number of real-valued multiplications per symbol of the proposed third-order WS-TNLE is significantly reduced to the same value as the number of weight-sharing kernels. When transmitting probabilistically shaped 16-level pulse amplitude modulation (PS-PAM-16) signals at net rates ranging from 200.4 Gb/s to 300.4 Gb/s over a 1-km standard single-mode fiber (SSMF), the proposed third-order WS-TNLE requires the lowest number of real-valued multiplications per symbol, ranging from 10 to 44, which reduces the computational complexity by up to 96.2% and 52.4% compared to the third-order WS-DP-VNLE and WS-DP-absolute-term nonlinear equalizer (WS-DP-ATNLE), respectively.

Engineering van der Waals Materials for Advanced Metaphotonics.

The outstanding chemical and physical properties of 2D materials, together with their atomically thin nature, make them ideal candidates for metaphotonic device integration and construction, which requires deep subwavelength light-matter interaction to achieve optical functionalities beyond conventional optical phenomena observed in naturally available materials. In addition to their intrinsic properties, the possibility to further manipulate the properties of 2D materials via chemical or physical engineering dramatically enhances their capability, evoking new science on light-matter interaction, leading to leaped performance of existing functional devices and giving birth to new metaphotonic devices that were unattainable previously. Comprehensive understanding of the intrinsic properties of 2D materials, approaches and capabilities for chemical and physical engineering methods, the resulting property modifications and novel functionalities, and applications of metaphotonic devices are provided in this review. Through reviewing the detailed progress in each aspect and the state-of-the-art achievement, insightful analyses of the outstanding challenges and future directions are elucidated in this cross-disciplinary comprehensive review with the aim to provide an overall development picture in the field of 2D material metaphotonics and promote rapid progress in this fast emerging and prosperous field.

C-band 100-GBaud PS-PAM-4 transmission over 50-km SSMF enabled by FIR-filter-based pre-electronic dispersion compensation.

Chromatic dispersion (CD) is always an obstacle to C-band high-speed intensity modulation and direct detection (IM/DD) transmissions, especially with a fiber reach of > 20 km. To reach beyond net-100-Gb/s IM/DD transmission over 50-km standard single mode fiber (SSMF), we for the first time present a CD-aware probabilistically shaped four-ary pulse amplitude modulation (PS-PAM-4) signal transmission scheme with a FIR-filter-based pre-electronic dispersion compensation (FIR-EDC) for C-band IM/DD transmission system. With the help of the FIR-EDC at the transmitter, 100-GBaud PS-PAM-4 signal transmission at 150-Gb/s line rate and 115.2-Gb/s net rate over 50-km SSMF is realized with only feed-forward equalization (FFE) at the receiver side. The superiority of the CD-aware PS-PAM-4 signal transmission scheme over other benchmark schemes has been successfully verified by experiments. Experimental results show that 24.5% improvement of system capacity is obtained by the FIR-EDC-based PS-PAM-4 signal transmission scheme in comparison to the FIR-EDC-based on-off keying (OOK) signal transmission scheme. Compared with the FIR-EDC-based uniform PAM-4 signal transmission scheme or the PS-PAM-4 signal transmission scheme without EDC, the capacity improvement obtained by the FIR-EDC-based PS-PAM-4 signal transmission scheme becomes more profound. The results show the potential and feasibility of such CD-aware PS-PAM-4 signal transmission scheme applied in CD-constrained IM/DD datacenter interconnects.

Signal processing integrated with fiber-optic Vernier effect for the simultaneous measurement of relative humidity and temperature.

A novel inline Fabry-Perot interferometer (FPI) for simultaneous relative humidity (RH) and temperature monitoring is proposed. The sensing probe consists of a section of hollow core Bragg fiber (HCBF) spliced with a single-mode fiber pigtail. The end-face of the HCBF is coated with Chitosan and ultraviolet optical adhesive (UVOA), forming two polymer layers using a well-designed fabrication process. The surfaces of the layers and splicing point will generate multiple-beam interference and form Vernier-effect (VE) related envelopes in the reflection spectrum. A signal processing (SP) method is proposed to demodulate the VE envelopes from a complicated superimposed raw spectrum. The principle of the SP algorithm is analyzed theoretically and verified experimentally. The sensor's RH and temperature response are studied, exhibiting a high sensitivity of about 0.437 nm/%RH and 0.29 nm/ ∘C, respectively. Using a matrix obtained from experiment results, the simultaneous RH and temperature measurement is achieved. Meanwhile, the simple fabrication process, compact size and potential for higher sensitivity makes our proposed structure integrated with the SP algorithm a promising sensor for practical RH and temperature monitoring.

Dynamic analysis of PAM-4 IM/DD OAM-based MGDM transmission enabled by mode-group filter approach.

Mode-group-division multiplexing (MGDM)-based intensity modulation direct detection (IM/DD) transmission is an attractive approach to increase the capacity for short-reach optical communication. In this Letter, a simple but versatile scheme of mode group (MG) filtering for MGDM IM/DD transmission is proposed. The scheme is applicable to any mode basis in the fiber, and it satisfies the needs of low complexity, low power consumption, and high system performance. By employing the proposed MG filter scheme, a total raw bit rate of a 152-Gb/s multiple-input-multiple-output (MIMO)-free IM/DD co-channel simultaneous transmit and receive system based on two orbital angular momentum (OAM) MGs, each carrying a 38-GBaud four-level pulse amplitude modulation (PAM-4) signal, is experimentally demonstrated over a 5-km few-mode fiber (FMF). The bit error ratios (BERs) of the two MGs are below the 7% hard-decision forward error correction (HD-FEC) BER threshold at 3.8×10-3, using simple feedforward equalization (FFE). Furthermore, the dependability and robustness of such MGDM links are of great significance. Thus, the dynamic evaluation of BER and signal-to-noise ratio (SNR) for each MG is tested over 210 minutes under different conditions. In the dynamic cases, all the BER results using the proposed scheme can be below 1×10-3, which further confirms the stability and feasibility of our proposed MGDM transmission scheme.

Highly sensitive gas pressure sensor based on the hollow core Bragg fiber and harmonic Vernier effect.

A highly sensitive inline gas pressure sensor based on the hollow core Bragg fiber (HCBF) and harmonic Vernier effect (VE) is proposed and experimentally demonstrated. By sandwiching a segment of HCBF between the lead-in single-mode fiber (SMF) and the hollow core fiber (HCF), a cascaded Fabry-Perot interferometer is produced. The lengths of the HCBF and HCF are precisely optimized and controlled to generate the VE, achieving a high sensitivity of the sensor. Meanwhile, a digital signal processing (DSP) algorithm is proposed to research the mechanism of the VE envelope, thus providing an effective way to improve the sensor's dynamic range based on calibrating the order of the dip. Theoretical simulations are investigated and matched well with the experimental results. The proposed sensor exhibits a maximum gas pressure sensitivity of 150.02 nm/MPa with a low temperature cross talk of 0.00235 MPa/ ∘C. All these advantages highlight the sensor's enormous potential for gas pressure monitoring under various extreme conditions.

Efficient 330-Gb/s PAM-8 modulation using silicon microring modulators.

We propose and demonstrate a high-efficiency silicon microring modulator for next-generation optical transmitters operating at line rates above 300 Gb/s. The modulator supports high-order PAM-8 modulation up to 110 Gbaud (330 Gb/s), with a driving voltage of 1.8 Vpp. The small driving voltage and device capacitance yields a dynamic energy consumption of 3.1 fJ/bit. Using the modulator, we compare PAM-8 with ultrahigh baud rate PAM-4 of up to 130 Gbaud (260 Gb/s) and show PAM-8 is better suited for 300-Gb/s lane rate operation in bandwidth-constrained short-reach systems.

Receive-diversity-aided power-fading compensation for C-band IM/DD OFDM systems.

A receive-diversity-aided power-fading compensation (RDA-PFC) scheme is proposed and demonstrated to eliminate the chromatic dispersion (CD)-induced power fading for C-band double-sideband (DSB) intensity modulation and direct detection (IM/DD) orthogonal frequency division multiplexing (OFDM) systems. By combining the responses before and after a dispersive element using a maximal-ratio combining (MRC) algorithm, the CD-induced power fading dips within the signal bandwidth of around 50 GHz can be effectively compensated for, which results in an up to 17.6-dB signal-to-noise ratio (SNR) improvement for the fading subcarriers after transmission over 10 km of standard single-mode fiber (SSMF). Using the 16 quadrature amplitude modulation (QAM) format, a diversity receiver with the proposed RDA-PFC scheme can support 170.6-Gbit/s OFDM signal transmission over a 10-km SSMF and reduces the bit error rate (BER) by more than an order of magnitude compared with a conventional receiver. Moreover, 208.1-Gbit/s adaptive bit and power loading OFDM signal transmission over a 10-km SSMF is realized by the proposed RDA-PFC scheme, which improves the capacity by 15.3% compared with the case without RDA-PFC at a BER of 3.8 × 10-3. The proposed RDA-PFC scheme shows great potential in CD-induced power-fading compensation for high-speed IM/DD OFDM systems.

Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging.

Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.

Fabry-Perot interferometers for highly-sensitive multi-point relative humidity sensing based on Vernier effect and digital signal processing.

A highly sensitive relative humidity (RH) sensor based on Fabry-Perot interferometers (FPI) is proposed and experimentally demonstrated. The sensor is fabricated by splicing a segment of hollow core Bragg fiber (HCBF) with single mode fiber (SMF) and functionalized with chitosan and ultraviolet optical adhesive (UVOA) composite at the end of HCBF to form a hygroscopic polymer film. The reflection beams from the splicing point and the two surfaces of the polymer film generate the Vernier effect in the reflection spectrum, which significantly improves the humidity sensitivity of the sensor. To demodulate the envelope based on the Vernier effect and realize multi-point sensing, a digital signal processing (DSP) algorithm is proposed to process the reflection spectrum. The performance of the DSP algorithm is theoretically analyzed and experimentally verified. The proposed sensor demonstrates a high sensitivity of 1.45 nm/% RH for RH ranging from 45% RH to 90% RH. The compact size, high sensitivity and multiplexing capability make this sensor a promising candidate for RH monitoring. Furthermore, the proposed DSP can potentially be applied to other sensors based on the Vernier effect to analyze and extract valuable information from the interference spectrum.

Comparison of low-complexity sparse and weight-sharing nonlinear equalizers for C-band 100-Gbit/s DSB PAM-4 transmission over 60-km SSMF.

To cope with the nonlinear distortions and the chromatic dispersion (CD) induced power fading in double-side band (DSB) intensity modulation and direct detection (IM/DD) transmission systems, high-performance Volterra nonlinear equalizers (VNLEs) including Volterra feed-forward equalizer (VFFE) and Volterra decision-feedback equalizer (VDFE) are widely applied. However, the conventional VNLEs have high computational complexity, especially for longer memory lengths. In this paper, based on sparse and weight-sharing strategies for significant kernel reduction, we propose four low-complexity NLEs including a sparse diagonally pruned VDFE (S-DP-VDFE), a sparse diagonally pruned absolute-term DFE (S-DP-ATDFE), a weight-sharing DP-VDFE (WS-DP-VDFE), and a weight-sharing DP-ATDFE (WS-DP-ATDFE), and present a comprehensive comparison among them in terms of computational complexity and bit error ratio (BER) performance in a C-band 100-Gbit/s PAM-4 transmission system over 60-km standard single-mode fiber (SSMF). The experimental results show that the proposed S-DP-VDFE and WS-DP-VDFE not only exhibit comparable performance with the conventional DP-VDFE but also reduce the complexity by 54.5% and 45.9%, respectively. While the proposed S-DP-ATDFE and WS-DP-ATDFE yield lower complexity at the expense of a slight performance degradation. Compared with the proposed S-DP-VDFE, S-DP-ATDFE, and WS-DP-VDFE, the proposed WS-DP-ATDFE with the lowest number of real-valued multiplications of 45 achieves up to 90.9%, 81.6%, and 95.8% complexity reduction, respectively, at the 7% hard-decision forward error correction (HD-FEC) BER limit of 3.8 × 10-3. The proposed low-complexity WS-DP-ATDFE shows great potential in low-cost and high-performance IM/DD optical transmission systems.

Compact 100GBaud driverless thin-film lithium niobate modulator on a silicon substrate.

Electro-optic (EO) modulators with a high modulation bandwidth are indispensable parts of an optical interconnect system. A key requirement for an energy-efficient EO modulator is the low drive voltage, which can be provided using a standard complementary metal oxide semiconductor circuity without an amplifying driver. Thin-film lithium niobate has emerged as a new promising platform, and shown its capable of achieving driverless and high-speed EO modulators. In this paper, we report a compact high-performance modulator based on the thin-film lithium niobate platform on a silicon substrate. The periodic capacitively loaded travelling-wave electrode is employed to achieve a large modulation bandwidth and a low drive voltage, which can support a driverless single-lane 100Gbaud operation. The folded modulation section design also helps to reduce the device length by almost two thirds. The fabricated device represents a large EO bandwidth of 45GHz with a half-wave voltage of 0.7V. The driverless transmission of a 100Gbaud 4-level pulse amplitude modulation signal is demonstrated with a power consumption of 4.49fj/bit and a bit-error rate below the KP4 forward-error correction threshold of 2.4×10-4.

Simple amplifier configuration algorithm for dynamic C + L-band systems in the presence of stimulated Raman scattering.

We propose a simple two-step amplifier configuration algorithm based on signal power across different channels to improve the generalized signal-to-noise ratio (GSNR) performance of dynamic C + L-band links in the presence of amplifier spontaneous emission (ASE) noise, Kerr nonlinearity, and stimulated Raman scattering (SRS) using erbium-doped fiber amplifiers (EDFA). In step 1, ASE noise and Kerr nonlinearity are taken into account to derive sub-optimal signal power profiles at the beginning of each span using the local optimization global optimization (LOGO) strategy. The effect of SRS is compensated through amplifier gain pre-tilt in step 2. Simulations for links with homogeneous/heterogeneous spans, static full-channel loading, and dynamic loading due to gradual channel additions for C + L-band upgrades show that the proposed algorithm can achieve similar GSNR performance, but requires much less execution time, compared to other iterative methods that target for improving the GSNR across the C + L band, thus making it a fast and efficient GSNR management strategy for future dynamic C + L-band networks.

C-band 120-Gb/s PAM-4 transmissions over a 100-km dispersion-uncompensated SSMF using joint combined pulse shaping and low-complexity nonlinear equalization.

In C-band intensity modulation and direct detection (IM/DD) systems, the frequency-dependent power fading induced by chromatic dispersion (CD) and square-law detection limits the transmission capacity and distance, especially for beyond 100-Gb/s transmissions over a 100-km dispersion-uncompensated link. To reach this goal, we propose a scheme of nonlinear pre-distortion, novel, to the best of our knowledge, combined pulse shaping, and post nonlinear equalization for four-level pulse amplitude modulation (PAM-4)-based IM/DD systems. At the transmitter, the nonlinear pre-distortion is used to generate unequally spaced PAM-4 symbols for pre-compensating the nonlinearities. While the novel pulse shaping, simply shaped by the linear combination of two inter-symbol interference (ISI)-free pulses, alters the frequency-domain power distribution of the PAM-4 signal and results in performance improvement. At the receiver, low-complexity post nonlinear equalization using an absolute-term based nonlinear equalizer with weight sharing (AT-NLE-WS) is performed to eliminate CD-induced power fading and residual nonlinear impairments. With the cooperation of these techniques, record 120-Gb/s PAM-4 signals are successfully transmitted over a 100-km standard single-mode fiber (SSMF) with the measured bit error ratio (BER) below 3.8 × 10-3, achieving >9% improvement of system capacity in comparison with the conventional pulse shaping schemes.

Low-complexity absolute-term based nonlinear equalizer with weight sharing for C-band 85-GBaud OOK transmission over a 100-km SSMF.

A low-complexity absolute-term based nonlinear feed-forward equalizer (FFE) combined with a decision-feedback equalizer (DFE) with weight sharing (AT-NLE-WS) is proposed and experimentally performed in a C-band 85-GBaud on-off keying (OOK) transmission system over a 100-km standard single-mode fiber (SSMF). By applying the k-means clustering algorithm to reduce weight redundancy, the required number of real-valued multiplications per symbol (RNRM) of the proposed AT-NLE-WS is only 14 for a bit error ratio (BER) under a KP4-forward error correction (FEC) threshold of 2.4 × 10-4. Compared with FFE-DFE, polynomial based nonlinear FFE-DFE (P-NLE), and AT-NLE, the proposed AT-NLE-WS saves >93% real-valued multiplications under the KP4-FEC threshold. In addition, compared with FFE-DFE, the proposed AT-NLE-WS can simultaneously achieve an approximately 2-dB improvement of receiver sensitivity and reduce the complexity by >80%. All experimental results show that AT-NLE-WS is a very attractive approach for practical implementation of low-cost optical interconnections with a data rate beyond 50 Gb/s and transmission distance up to 100 km.

C-band 67†GHz silicon photonic microring modulator for dispersion-uncompensated 100 Gbaud PAM-4.

A very-high-bandwidth integrated silicon microring modulator (MRM) designed on a commercial silicon photonics (SiP) platform for C-band operation is presented. The MRM has a 3 dB electro-optic (EO) bandwidth of over 67 GHz and features a small footprint of 24 µm × 70 µm. Using the MRM, we demonstrate intensity modulation-direct detection (IM-DD) transmission with 4-level pulse amplitude modulation (PAM-4)  signaling of over 100 Gbaud. By utilizing the optical peaking effect and negative chirp in the MRM, we extend the transmission distance, which is limited by the fiber-dispersion-induced frequency fading. Using a standard single-mode fiber (SSMF) for transmission across distances of up to 2 km, we measured the data transmission of 100 Gbaud PAM-4 signals with a bit error rate (BER) under the general 7% hard-decision forward-error correction (HD-FEC) threshold. The MRM enables an extended transmission distance for 100 Gbaud signaling in the C-band without dispersion compensation.

Nonlinearity-aware PS-PAM-16 transmission for C-band net-300-Gbit/s/λ short-reach optical interconnects with a single DAC.

A nonlinearity-aware signal transmission scheme based on a low-complexity 3rd-order diagonally pruned absolute-term nonlinear equalizer (NLE) with weight sharing (DP-AT-NLE-WS) and rate-adaptable probabilistically shaped 16-level pulse amplitude modulation (PS-PAM-16) signal is proposed and experimentally demonstrated for C-band net-300-Gbit/s/λ short-reach optical interconnects. By replacing the multiplication operation with the absolute operation and applying weight sharing to reduce the kernel redundancy, the computational complexity of the proposed 3rd-order DP-AT-NLE-WS is reduced by >40% compared with the 3rd-order DP-Volterra NLE (DP-VNLE), DP-AT-NLE, and DP-VNLE-WS, with the achieved normalized general mutual information (NGMI) above a threshold of 0.857. Employing a commercial 32-GHz Mach-Zehnder modulator (MZM) and a single digital-to-analog converter (DAC), we demonstrate the single-lane transmission of 100-GBaud PS-PAM-16 signal using DP-AT-NLE-WS in the C band at record 370-Gbit/s line rate and 300.4-Gbit/s net rate over 1-km standard single-mode fiber (SSMF), achieving 21.2% (15.5%) capacity improvement over 100 (105)-GBaud PAM-8 transmission. To the best of our knowledge, this is the first net-300-Gbit/s intensity modulation and direct detection (IM/DD) short-reach transmission in the C band using commercially available components.

SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer.

Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), occur with high frequency in breast cancer. The protein kinase Akt is considered to be the primary effector of PIK3CA, although mechanisms by which PI3K mediates Akt-independent tumorigenic signals remain obscure. We show that serum and glucocorticoid-regulated kinase 3 (SGK3) is amplified in breast cancer and activated downstream of PIK3CA in a manner dependent on the phosphoinositide phosphatase INPP4B. Expression of INPP4B leads to enhanced SGK3 activation and suppression of Akt phosphorylation. Activation of SGK3 downstream of PIK3CA and INPP4B is required for 3D proliferation, invasive migration, and tumorigenesis in vivo. We further show that SGK3 targets the metastasis suppressor NDRG1 for degradation by Fbw7. We propose a model in which breast cancers harboring oncogenic PIK3CA activate SGK3 signaling while suppressing Akt, indicative of oncogenic functions for both INPP4B and SGK3 in these tumors.

SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.

BACKGROUND: Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. METHODS: We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. RESULTS: SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. CONCLUSION: SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.