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.

Relevance of ATM Status in Driving Sensitivity to DNA Damage Response Inhibitors in Patient-Derived Xenograft Models.

Ataxia-telangiectasia mutated gene (ATM) is a key component of the DNA damage response (DDR) and double-strand break repair pathway. The functional loss of ATM (ATM deficiency) is hypothesised to enhance sensitivity to DDR inhibitors (DDRi). Whole-exome sequencing (WES), immunohistochemistry (IHC), and Western blotting (WB) were used to characterise the baseline ATM status across a panel of ATM mutated patient-derived xenograft (PDX) models from a range of tumour types. Antitumour efficacy was assessed with poly(ADP-ribose)polymerase (PARP, olaparib), ataxia- telangiectasia and rad3-related protein (ATR, AZD6738), and DNA-dependent protein kinase (DNA-PK, AZD7648) inhibitors as a monotherapy or in combination to associate responses with ATM status. Biallelic truncation/frameshift ATM mutations were linked to ATM protein loss while monoallelic or missense mutations, including the clinically relevant recurrent R3008H mutation, did not confer ATM protein loss by IHC. DDRi agents showed a mixed response across the PDX's but with a general trend toward greater activity, particularly in combination in models with biallelic ATM mutation and protein loss. A PDX with an ATM splice-site mutation, 2127T > C, with a high relative baseline ATM expression and KAP1 phosphorylation responded to all DDRi treatments. These data highlight the heterogeneity and complexity in describing targetable ATM-deficiencies and the fact that current patient selection biomarker methods remain imperfect; although, complete ATM loss was best able to enrich for DDRi sensitivity.

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.

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.

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.

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.

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.

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.

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.

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.

Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance.

PURPOSE: PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. EXPERIMENTAL DESIGN: We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. RESULTS: Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. CONCLUSIONS: Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi.

Guillain-Barré syndrome in children - High occurrence of Miller Fisher syndrome in East Asian region.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare acquired immune-mediated polyneuropathy. Updated population-based data concerning paediatric GBS is needed. METHODS: Paediatric patients aged below 18 years diagnosed with GBS between 2009 and 2018 in all 11 paediatric departments in Hong Kong were identified from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. The collected data from medical health records were reviewed by paediatric neurologist from each department. Estimated incidence of paediatric GBS was calculated. We also compared our findings with other paediatric GBS studies in Asia. RESULTS: 63 subjects of paediatric GBS were identified, giving an estimated annual incidence of 0.62 per 100,000 population. Half of the subjects had acute inflammatory demyelinating polyneuropathy (AIDP) (n = 31; 49.2%), one quarter had Miller Fisher Syndrome (MFS) (n = 16; 25.4%), one-fifth had axonal types of GBS (n = 12; 19.0%), and four were unclassified. Paediatric subjects with axonal subtypes of GBS compared to the other 2 subtypes, had significantly higher intensive care unit (ICU) admission rates (p = 0.001) and longest length of stay (p = 0.009). With immunomodulating therapy, complete recovery was highest in those with MFS (100%), followed by AIDP (87.1%) and axonal GBS (75%). Our study also confirms a higher MFS rate for paediatric GBS in East Asia region and our study has the highest MFS rate (25.4%). CONCLUSION: Our population-based 10-year paediatric GBS study provides updated evidence on estimated incidence, healthcare burden and motor outcome of each subtype of paediatric GBS and confirmed a higher occurrence of paediatric MFS in East Asia.

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.

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.

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.

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.

ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib.

AZD6738 (ceralasertib) is a potent and selective orally bioavailable inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. ATR is activated in response to stalled DNA replication forks to promote G2-M cell-cycle checkpoints and fork restart. Here, we found AZD6738 modulated CHK1 phosphorylation and induced ATM-dependent signaling (pRAD50) and the DNA damage marker γH2AX. AZD6738 inhibited break-induced replication and homologous recombination repair. In vitro sensitivity to AZD6738 was elevated in, but not exclusive to, cells with defects in the ATM pathway or that harbor putative drivers of replication stress such as CCNE1 amplification. This translated to in vivo antitumor activity, with tumor control requiring continuous dosing and free plasma exposures, which correlated with induction of pCHK1, pRAD50, and γH2AX. AZD6738 showed combinatorial efficacy with agents associated with replication fork stalling and collapse such as carboplatin and irinotecan and the PARP inhibitor olaparib. These combinations required optimization of dose and schedules in vivo and showed superior antitumor activity at lower doses compared with that required for monotherapy. Tumor regressions required at least 2 days of daily dosing of AZD6738 concurrent with carboplatin, while twice daily dosing was required following irinotecan. In a BRCA2-mutant patient-derived triple-negative breast cancer (TNBC) xenograft model, complete tumor regression was achieved with 3 to5 days of daily AZD6738 per week concurrent with olaparib. Increasing olaparib dosage or AZD6738 dosing to twice daily allowed complete tumor regression even in a BRCA wild-type TNBC xenograft model. These preclinical data provide rationale for clinical evaluation of AZD6738 as a monotherapy or combinatorial agent. SIGNIFICANCE: This detailed preclinical investigation, including pharmacokinetics/pharmacodynamics and dose-schedule optimizations, of AZD6738/ceralasertib alone and in combination with chemotherapy or PARP inhibitors can inform ongoing clinical efforts to treat cancer with ATR inhibitors.

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.