Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors.

Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.

The effect of subsequent pregnancy and childbirth on stress urinary incontinence recurrence following midurethral sling procedure: a meta-analysis.

OBJECTIVE: This study aimed to assess the risk of stress urinary incontinence recurrence and reoperation after a midurethral sling procedure in women with subsequent childbirth and to assess the effect of delivery mode on this risk. DATA SOURCES: An electronic database search was performed using MEDLINE with the OvidSP interface and PubMed, Embase, Web of Science, and the Cochrane Library up to September 20, 2023. STUDY ELIGIBILITY CRITERIA: This study included experimental and nonexperimental studies, composed of randomized controlled and observational (case-control, cohort, and cross-sectional) studies assessing the risk factors for stress urinary incontinence recurrence and reoperation after childbirth in women who had previously undergone a midurethral sling procedure for stress urinary incontinence. METHODS: Analysis was performed using RevMan (version 5.3; Cochrane Collaboration, Oxford, United Kingdom). Quantitative synthesis was used if the included studies were sufficient in numbers and homogeneity. The overall certainty of the evidence was assessed using criteria recommended by the Grading of Recommendations Assessment, Development, and Evaluation Working Group. RESULTS: A total of 2001 studies were identified, of which 6 were eligible for analysis, composed of 381 patients who had at least 1 childbirth after a midurethral sling procedure (study group) and 860 patients who underwent a midurethral sling without having a subsequent childbirth (control group). All included studies were observational, the patients' mean age at the time of the midurethral sling procedure ranged from 34 to 36 years, and the mean time from midurethral sling procedure to delivery ranged from 21 to 31 months. No difference in stress urinary incontinence recurrence (relative risk, 0.1.02; 95% confidence interval, 0.78-1.33) or reoperation (relative risk, 1.37; 95% confidence interval, 0.87-2.17) was found between the study and control groups. The average follow-up time among the included studies of this comparison was 9.8 years (range, 2-18). Furthermore, the mode of delivery (vaginal vs cesarean) did not seem to affect the risk of stress urinary incontinence recurrence. CONCLUSION: Subsequent pregnancy and childbirth did not increase the risk of stress urinary incontinence recurrence or reoperation after a midurethral sling procedure.

Pain and anxiety management with virtual reality for office hysteroscopy: systemic review and meta-analysis.

PURPOSE: Office hysteroscopy (OH) is a commonly performed procedure, although it might be associated with some degree of pain and anxiety. Our aim was to determine the effects of virtual reality on pain and anxiety levels felt by patients undergoing OH. METHODS: MEDLINE, Embase, Google Scholar, Cochrane Library, clinicaltrials.gov, ProQuest, Grey literature, and manual searching of references within studies found in the initial search were systematically searched using the terms 'Virtual Reality' and 'Hysteroscopy' without time or language limitations. The review considered all studies assessing the impact of virtual reality (VR) over OH outcomes, and prospective randomized trials were included in the meta-analysis. Retrospective and case - control studies were excluded from the meta-analysis. RESULTS: We identified 17 studies, of which four randomized controlled studies were included in the meta-analysis (327 participants, 168 in the VR group and 159 in the control group). On a 0-10 scale, pain sensation and maximal pain sensation during the operation were not statistically different between study and control groups (relative risk (RR) = -0.64, 95% C.I (-1.57)0.29) and (RR = -0.93, 95% C.I (-3.33) - 1.47), respectively. Anxiety measurement was statistically lower in the study group (RR = -1.73, 95% C.I (-2.79) - ( -0.67)). CONCLUSIONS: The available data suggest that VR techniques do not decrease the pain sensation during OH however, they do contribute to a reduction in the anxiety levels experienced by patients. PROSPERO registration number CRD42023432819.

Stress-Induced Proteasome Sub-Cellular Translocation in Cardiomyocytes Causes Altered Intracellular Calcium Handling and Arrhythmias.

The ubiquitin-proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work. Following a recent study by Ciechanover's group showing that amino acid (AA) starvation in cultured cancer cell lines modulates proteasome intracellular localization and activity, we tested two hypotheses in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs, CMs): (i) AA starvation causes proteasome translocation in CMs, similarly to the observation in cultured cancer cell lines; (ii) manipulation of subcellular proteasomal compartmentalization is associated with electrophysiological abnormalities in the form of arrhythmias, mediated via altered intracellular Ca2+ handling. The major findings are: (i) starving CMs to AAs results in proteasome translocation from the nucleus to the cytoplasm, while supplementation with the aromatic amino acids tyrosine (Y), tryptophan (W) and phenylalanine (F) (YWF) inhibits the proteasome recruitment; (ii) AA-deficient treatments cause arrhythmias; (iii) the arrhythmias observed upon nuclear proteasome sequestration(-AA+YWF) are blocked by KB-R7943, an inhibitor of the reverse mode of the sodium-calcium exchanger NCX; (iv) the retrograde perfusion of isolated rat hearts with AA starvation media is associated with arrhythmias. Collectively, our novel findings describe a newly identified mechanism linking the UPS to arrhythmia generation in CMs and whole hearts.

Brain-wide structural and functional disruption in mice with oligodendrocyte-specific Nf1 deletion is rescued by inhibition of nitric oxide synthase.

Neurofibromin gene (NF1) mutation causes neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocytes causes myelin decompaction and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brain-wide structure and account for NF1 imaging findings is unknown. Here we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice showed that fractional anisotropy is reduced in Plp-Nf1fl/+ corpus callosum and that interhemispheric functional connectivity in the motor cortex is also reduced, consistent with disrupted myelin integrity. Furthermore, NOS-specific inhibition rescued both measures. These results suggest that oligodendrocyte defects account for aspects of brain dysfunction in NF1 that can be identified by neuroimaging and ameliorated by NOS inhibition.

Does vaginal cleansing with iodine decreases infection rate in office hysteroscopy?

PURPOSE: To determine whether preoperative vaginal cleansing with iodine-based solution prior to hysteroscopy, reduces postoperative infection rate compared to no vaginal cleansing. METHODS: A retrospective study at a single tertiary, university affiliated hospital of all individuals who have had an office hysteroscopy. Study group consisted of patients who have had preoperative vaginal cleansing with iodine-based solution and were compared to those who have not. Any procedural related complaints at the 30 days following the hysteroscopy were recorded. RESULTS: A total of 505 were available for analysis, 183 in the study group and 322 in the control group. The most common indications for operation were infertility evaluation (33.9% vs. 28.6%) and retained products of conception (33.3% vs. 29.2%), and most common procedures were diagnostic only (49.7% vs. 42.5%) followed by adhesiolysis (12% vs. 14.3%). No statistical differences were noted with regards to postoperative infections, as only one case of pelvic inflammatory disease was noted, in the iodine cleansing group (0.19% for postoperative infection). CONCLUSION: Our comparative study may suggest that the use of preoperative iodine solution prior to office hysteroscopy does not decrease the postoperative infection rate up to 30 days, thus can be avoided.

The Value of Preoperative Multichannel Urodynamic Testing for Detecting Occult Stress Urinary Incontinence in Women Undergoing Prolapse Repair Surgery.

BACKGROUND: Diagnosing occult stress urinary incontinence (OSUI) prior to surgical intervention for pelvic organ prolapse (POP) repair may allow for adding an anti-incontinence procedure and thus prevent postoperative SUI. OBJECTIVES: To compare preoperative detection rates for OSUI by either a multichannel urodynamic investigation or by a plain pelvic examination. METHODS: We retrospectively evaluated the medical charts of all women who underwent urodynamic investigation prior to surgical repair of advanced POP at our institution between 1 January 2006 and 31 December 2012. RESULTS: In total, 720 women underwent surgical POP repair during the study period, of whom 54 (7.5%) were diagnosed with OSUI preoperatively. Of these patients, 54 (100%) were detected by multichannel urodynamic investigation while only 27 (50%) were detected by a plain pelvic examination (P = 0.001). Bladder fullness during the pelvic examination was associated with higher detection rates for OSUI (P = 0.001). Women with OSUI who underwent concomitant tension-free vaginal tape and POP repair procedures did not develop de novo SUI or obstructive voiding symptoms (OVS) postoperatively. CONCLUSIONS: Preoperative multichannel urodynamic investigation has significantly higher detection rates for OSUI than a plain pelvic examination. Utilizing this modality resulted in no cases of de novo SUI or OVS postoperatively.

When Do Women with Second Trimester Pregnancy Loss Need Repeated Doses of Misoprostol? Insights from a Teaching Hospital.

BACKGROUND: Cases of second trimester pregnancy loss can be treated either pharmacologically or by surgical evacuation. Misoprostol, an E1-prostaglandin analog, is used to facilitate the evacuation of the uterus. OBJECTIVES: To determine the risk factors associated with patients who were treated with five or more repeated doses of misoprostol. METHODS: We conducted a retrospective study of patients treated with vaginal misoprostol at our institution between December 2016 and October 2021 for second trimester pregnancy loss. RESULTS: In total, 114 patients were eligible for analysis; 83 were treated with < 5 doses and 31 with ≥ 5. We recorded each case in which repeated doses were administered, irrespective of predetermined conditions such as gravidity, parity, maternal age, or gestational age. Moreover, cases of five or more misoprostol dosing were not associated with an increased complications rate, except for the increased duration of hospitalization (3.1 vs. 2.2 days, P-value < 0.01). CONCLUSIONS: Repeated dosing could not be predicted before treatment among those treated with vaginally administered misoprostol for second trimester pregnancy loss. However, low complication rates of repeated dosing may reassure both physicians and patients regarding safety, efficacy, and future fertility.

Group B Streptococcus real-time PCR may potentially reduce intrapartum maternal antibiotic treatment.

BACKGROUND: Protocols for preventing early-onset group B streptococcal (GBS) neonatal infection may result in unnecessary antibiotics administration. Real-time polymerase chain reaction (PCR) can provide a result within 30-60 min and has been found to be specific and sensitive for defining intrapartum GBS status. OBJECTIVE: To evaluate whether implementation of GBS fast real-time PCR to all women who require GBS prophylaxis may reduce the use of maternal prophylactic antibiotics. METHODS: This prospective cohort study included women admitted to a single delivery ward who required prophylactic antibiotics either due to a positive antepartum GBS culture screening performed at 35-37 weeks or due to an unknown GBS status with an intrapartum risk factor. All the women were tested by a double vaginal swab (real-time PCR and culture) as soon as it became apparent, they required antibiotic prophylaxis and prior to its administration. RESULTS: Between May 2019 and August 2020, 303 women met eligibility criteria and were enrolled, but four were excluded from the analysis due to failed culture or PCR tests. Of 299 women included in the study, 208 (69.5%) and 180 (60.2%) women, showed no evidence of GBS on intrapartum culture or PCR, respectively. Of 89 GBS antepartum carriers, 43 (48.3%) and 32 (35.9%) had negative intrapartum culture and PCR results, respectively. Of the 210 women with risk factors, 165 (78.5%) were culture negative and 148 (70.4%) had a negative PCR. Using intrapartum culture as the gold standard, intrapartum GBS real-time PCR was found to have a sensitivity of 97.8% (95% confidence interval [CI] 92.3, 99.7) and a specificity of 85.6% (95% CI 80.1, 90.1). CONCLUSIONS: Compared with antepartum universal culture screening or intrapartum risk-factor assessment, the need for maternal antibiotic treatment may be substantially reduced by implementation of intrapartum GBS real-time PCR, without compromising the sensitivity of GBS detection.

Enhanced Recovery after Surgery is Feasible and Beneficial and Should Be the Standard in Major Gynecological Surgeries.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are evidence-based protocols designed to standardize medical care, improve outcomes, and lower healthcare costs. OBJECTIVES: To evaluate the implementation of the ERAS protocol and the effect on recovery during the hospitalization period after gynecological laparotomy surgeries. METHODS: We compared demographic and clinical data of consecutive patients at a single institute who underwent open gynecological surgeries before (August 2017 to December 2018) and after (January 2019 to March 2020) the implementation of the ERAS protocol. Eighty women were included in each group. RESULTS: The clinical and demographic characteristics were similar among the women operated before and after implementation of the ERAS protocol. Following implementation of the protocol, decreases were observed in post-surgical hospitalization (from 4.89 ± 2.56 to 4.09 ± 1.65 days, P = 0.01), in patients reporting nausea symptoms (from 18 (22.5%) to 7 (8.8%), P = 0.017), and in the use of postoperative opioids (from 77 (96.3%) to 47 (58.8%), P < 0.001). No significant changes were identified between the two periods regarding vomiting, 30-day re-hospitalization, and postoperative minor and major complications. CONCLUSIONS: Implementation of the ERAS protocol is feasible and was found to result in less postoperative opioid use, a faster return to normal feeding, and a shorter postoperative hospital stay. Implementation of the protocol implementation was not associated with an increased rate of complications or with re-admissions.

Demonstrating the use of OAM modes to facilitate the networking functions of carrying channel header information and orthogonal channel coding.

We experimentally demonstrate the use of orbital angular momentum (OAM) modes as a degree of freedom to facilitate the networking functions of carrying header information and orthogonal channel coding. First, for carrying channel header information, we transmit a 10 Gb/s on-off keying (OOK) data channel as a Gaussian beam and add to it a 10 Mb/s OOK header carried by an OAM beam with the mode order ℓ=3. We recover the header and use it to drive a switch and select the output port. Secondly, for orthogonal channel coding, we configure transmitters to generate orthogonal spatial codes (orthogonal spatial beam profiles of OAM modes), each carrying an independent data stream. We measure the correlation between the OAM codes and demonstrate their use in a multiple access system carrying two 10 Gb/s OOK data channels. At the end of this Letter, we combine the concepts of using OAM modes for carrying channel header information and orthogonal channel coding in one experiment. We transmit a 10 Gb/s OOK data channel as a Gaussian beam and add to it two 10 Mb/s OOK header waveforms carried by different OAM codes. In the routing node, we recover one of the headers to drive the switch.

Experimental mitigation of the effects of the limited size aperture or misalignment by singular-value-decomposition-based beam orthogonalization in a free-space optical link using Laguerre-Gaussian modes.

Limited-size receiver (Rx) apertures and transmitter-Rx (Tx-Rx) misalignments could induce power loss and modal crosstalk in a mode-multiplexed free-space link. We experimentally demonstrate the mitigation of these impairments in a 400 Gbit/s four-data-channel free-space optical link. To mitigate the above degradations, our approach of singular-value-decomposition-based (SVD-based) beam orthogonalization includes (1) measuring the transmission matrix H for the link given a limited-size aperture or misalignment; (2) performing SVD on the transmission matrix to find the U, Σ, and V complex matrices; (3) transmitting each data channel on a beam that is a combination of Laguerre-Gaussian modes with complex weights according to the V matrix; and (4) applying the U matrix to the channel demultiplexer at the Rx. Compared with the case of transmitting each channel on a beam using a single mode, our experimental results when transmitting multi-mode beams show that (a) with a limited-size aperture, the power loss and crosstalk could be reduced by ∼8 and ∼23dB, respectively; and (b) with misalignment, the power loss and crosstalk could be reduced by ∼15 and ∼40dB, respectively.

"Hiding" a low-intensity 50 Gbit/s QPSK free-space OAM beam using an orthogonal coaxial high-intensity 50 Gbit/s QPSK beam.

In this paper, we experimentally demonstrate an approach that "hides" a low-intensity 50 Gbit/s quadrature-phase-keying (QPSK) free-space optical beam when it coaxially propagates on the same wavelength with an orthogonal high-intensity 50 Gbit/s QPSK optical beam. Our approach is to coaxially transmit the strong and weak beams carrying different orthogonal spatial modes within a modal basis set, e.g., orbital angular momentum (OAM) modes. Although the weak beam has much lower power than that of the strong beam, and the beams are in the same frequency band and on the same polarization, the two beams can still be effectively demultiplexed with little inherent crosstalk at the intended receiver due to their spatial orthogonality. However, an eavesdropper may not readily identify the weak beam when simply analyzing the spatial intensity profile. The correlation coefficient between the intensity profiles of the strong beam and the combined strong and weak beams is measured to characterize the potential for "hiding" a weak beam when measuring intensity profiles. Such a correlation coefficient is demonstrated to be higher than 0.997 when the power difference between the strong fundamental Gaussian beam and the weak OAM beam is ∼8,∼10, and ∼10dB for the weak OAM -1,-2, and -3 beams, respectively. Moreover, a 50 Gbit/s QPSK data link having its Q factor above the 7% forward error correction limit is realized when the power of the weak OAM -3 beam is 30 dB lower than that of the strong fundamental Gaussian beam.

Quantum Entanglement in Deep Learning Architectures.

Modern deep learning has enabled unprecedented achievements in various domains. Nonetheless, employment of machine learning for wave function representations is focused on more traditional architectures such as restricted Boltzmann machines (RBMs) and fully connected neural networks. In this Letter, we establish that contemporary deep learning architectures, in the form of deep convolutional and recurrent networks, can efficiently represent highly entangled quantum systems. By constructing tensor network equivalents of these architectures, we identify an inherent reuse of information in the network operation as a key trait which distinguishes them from standard tensor network-based representations, and which enhances their entanglement capacity. Our results show that such architectures can support volume-law entanglement scaling, polynomially more efficiently than presently employed RBMs. Thus, beyond a quantification of the entanglement capacity of leading deep learning architectures, our analysis formally motivates a shift of trending neural-network-based wave function representations closer to the state-of-the-art in machine learning.

Experimental utilization of repeated spatial-mode shifting for achieving discrete delays in a free-space recirculating loop.

We demonstrate an optical recirculating delay loop by shifting the spatial mode order of orbital-angular-momentum (OAM) beams in the free-space. The desired delay can be selected at the loop output by exploiting the orthogonality of the OAM modes. When sending a 20-Gbaud quadrature-phase-shift-keyed (QPSK) signal through the delay system, three recirculations are demonstrated, each with an additional delay of 2.2 ns. Around 0.5 and 2 dB system penalties are measured for the second and third recirculations, respectively. We also simulate the performance of our approach under different scenarios.

Molecular Mechanism for LAMP1 Recognition by Lassa Virus.

UNLABELLED: Lassa virus is a notorious human pathogen that infects many thousands of people each year in West Africa, causing severe viral hemorrhagic fevers and significant mortality. The surface glycoprotein of Lassa virus mediates receptor recognition through its GP1 subunit. Here we report the crystal structure of GP1 from Lassa virus, which is the first representative GP1 structure for Old World arenaviruses. We identify a unique triad of histidines that forms a binding site for LAMP1, a known lysosomal protein recently discovered to be a critical receptor for internalized Lassa virus at acidic pH. We demonstrate that mutation of this histidine triad, which is highly conserved among Old World arenaviruses, impairs LAMP1 recognition. Our biochemical and structural data further suggest that GP1 from Lassa virus may undergo irreversible conformational changes that could serve as an immunological decoy mechanism. Together with a variable region that we identify on the surface of GP1, those could be two distinct mechanisms that Lassa virus utilizes to avoid antibody-based immune response. IMPORTANCE: Structural data at atomic resolution for viral proteins is key for understanding their function at the molecular level and can facilitate novel avenues for combating viral infections. Here we used X-ray protein crystallography to decipher the crystal structure of the receptor-binding domain (GP1) from Lassa virus. This is a pathogenic virus that causes significant illness and mortality in West Africa. This structure reveals the overall architecture of GP1 domains from the group of viruses known as the Old World arenaviruses. Using this structural information, we elucidated the mechanisms for pH switch and binding of Lassa virus to LAMP1, a recently identified host receptor that is critical for successful infection. Lastly, our structural analysis suggests two novel immune evasion mechanisms that Lassa virus may utilize to escape antibody-based immune response.

Early wound dressing removal after scheduled cesarean delivery: a randomized controlled trial.

BACKGROUND: Following cesarean delivery, wound dressings are typically left over the incision for 24-48 hours. OBJECTIVE: The objective of this study was to determine if early removal of the wound dressing at 6 hours postsurgery has any effect on wound complications. STUDY DESIGN: This was a randomized, controlled study from August 2013 through January 2015 in which 320 low-risk women aged 18-44 years having scheduled primary, first repeat, or second repeat cesarean delivery were randomized for wound dressing removal at either 6 or 24 hours postsurgery. Skin closure was with staples in all cases. The primary outcome was postoperative wound complications, defined as infection, disruption (skin dehiscence or deeper), or seroma/hematoma. Also examined was patient satisfaction with timing of their ability to wash or shower after wound dressing removal. A sample size of 160 women in each group was needed to show a 100% increase in the wound complication incidence from 12-24%. RESULTS: A total of 320 women were randomized, 160 in the 6-hour group and 160 in the 24-hour group. The proportion of primary and repeat cesarean deliveries was similar. The incidence of wound complications was not significantly different between the groups, 13.8% in the 6-hour group and 12.5% in the 24-hour group (odds ratio, 1.16; 95% confidence interval, 0.58-2.14). More women were pleased and satisfied with their ability to wash or shower soon after wound dressing removal in the 6-hour group (75.6%) compared to the 24-hour group (56.9%; odds ratio, 2.35; 95% confidence interval, 1.46-3.79). CONCLUSION: Early removal of the wound dressing at 6 hours following cesarean delivery has no detrimental effect on incision healing. Early removal permits the woman to attend to personal hygiene earlier, making her more satisfied with her postoperative recovery.

Doppler-based flow rate sensing in microfluidic channels.

We design, fabricate and experimentally demonstrate a novel generic method to detect flow rates and precise changes of flow velocity in microfluidic devices. Using our method we can measure flow rates of ~2 mm/s with a resolution of 0.08 mm/s. The operation principle is based on the Doppler shifting of light diffracted from a self-generated periodic array of bubbles within the channel and using self-heterodyne detection to analyze the diffracted light. As such, the device is appealing for variety of "lab on chip" bio-applications where a simple and accurate speed measurement is needed, e.g., for flow-cytometry and cell sorting.

Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.

Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.