Cancer associated fibroblasts serve as an ovarian cancer stem cell niche through noncanonical Wnt5a signaling.

Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increase OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures and in vivo limiting dilution assay, we confirm that the CAFs act by enriching the CSC population. CAFs increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs is limited to OC cells in their immediate neighborhood, which can be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients reveal Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. Our findings demonstrate that Wnt5a from CAFs activate a noncanonical Wnt signaling pathway involving the ROR2/PKC/CREB1 axis in the neighboring CSCs. While canonical Wnt signaling is found to be predominant in interactions between cancer cells in patients, non-canonical Wnt pathway is activated by the CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitizes tumors to carboplatin in vivo. Together, our results demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.

SGLT2 Inhibitor Use and Risk of Breast Cancer Among Adult Women with Type 2 Diabetes.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic agents, with the potential to inhibit breast cancer development. However, the association between SGLT2 inhibitors and risk of breast cancer in human studies is unclear. OBJECTIVE: The aim of our study is to use a large national claims database to assess the association between SGLT2 inhibitor use and risk of breast cancer. METHODS: We considered a study population of 158,483 adult women with type 2 diabetes who newly initiated SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP4) inhibitors using Optum's deidentified Clinformatics Data Mart Database between 1 January 2013 and 31 March 2022. The association between SGLT2 inhibitor use and risk of breast cancer was examined using Cox proportional hazard models stratified by age in the overall sample and in a subsample based on propensity score and medication initiation time matching. The effect of medication use duration was explored. RESULTS: With an average follow-up of 2.2 years, 2154 breast cancer cases were identified. There was no significant association between SGLT2 inhibitor use and the risk of breast cancer in overall sample (HR = 0.96; 95% CI 0.87, 1.06), in women younger than 51 years old (HR = 0.88; 95% CI 0.59, 1.32), or in women aged 51 years or older (HR = 0.95; 95% CI 0.86, 1.04). The results remained nonsignificant using matching, medication use duration, and sensitivity analyses. CONCLUSION: Our findings suggest SGLT2 inhibitors use was not associated with breast cancer risk compared with DPP4 inhibitors use. Studies with longer follow-up and better adjustments are needed to confirm the finding.

Allostatic load and risk of invasive breast cancer among postmenopausal women in the U.S.

OBJECTIVE: Allostatic load can reflect the body's response to chronic stress. However, little is known about the association between allostatic load and risk of breast cancer in postmenopausal women. This study used a large prospective cohort in the United States to examine the relationship between allostatic load and invasive breast cancer risk, and to evaluate the relationship by racial and ethnic identity and breast cancer subtypes. METHODS: Among 161,808 postmenopausal participants in Women's Health Initiative, eligible were a subsample of 27,393 postmenopausal women aged 50-79 years old, who enrolled from 1993 to 1998, had serum test biomarkers, and were followed for breast cancer incidence through February 2022. Allostatic load at enrollment was computed based on eight biomarkers from lab serum tests and a questionnaire about participants' prescription drug use. The associations between allostatic scores and risk of breast cancer (overall and by subtypes) were assessed using Cox proportional hazards models. The race and ethnic differences were examined. RESULTS: Over a median follow-up time of 17.24 years, 1722 invasive breast cancer cases were identified. High allostatic load was associated with an increased risk of breast cancer (HR = 1.36, 95%CI: 1.20, 1.54 for third tertile vs first tertile, Ptrend < 0.0001). Similar trends were found in White women and non-Hispanic women. Higher allostatic load was associated with hormone receptor-positive and HER2/Neu-negative breast cancer (HR = 1.54, 95%CI: 1.30, 1.80 for third tertile vs first tertile, Ptrend < 0.0001). CONCLUSION: In this study, we found that higher allostatic load was significantly associated with an increased risk of breast cancer in postmenopausal women.

Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer.

Ovarian cancer is the deadliest gynecological malignancy with a high prevalence of transcoelomic metastasis. Metastasis is a multi-step process and only a small percentage of cancer cells, metastasis-initiating cells (MICs), have the capacity to finally establish metastatic lesions. These MICs maintain a certain level of stemness that allows them to differentiate into other cell types with distinct transcriptomic profiles and swiftly adapt to external stresses. Furthermore, they can coordinate with the microenvironment, through reciprocal interactions, to invade and establish metastases. Therefore, identifying, characterizing, and targeting MICs is a promising strategy to counter the spread of ovarian cancer. In this review, we provided an overview of OC MICs in the context of characterization, identification through cell surface markers, and their interactions with the metastatic niche to promote metastatic colonization.

Rho-dependent transcription termination is the dominant mechanism in Mycobacterium tuberculosis.

Intrinsic and Rho-dependent transcription termination mechanisms regulate gene expression and recycle RNA polymerase in bacteria. Both the modes are well studied in Escherichia coli, and a few other organisms. The understanding of Rho function is limited in most other bacteria including mycobacteria. Here, we highlight the dominance of Rho-dependent termination in mycobacteria and validate Rho as a key regulatory factor. The lower abundance of intrinsic terminators, high cellular levels of Rho, and its genome-wide association with a majority of transcriptionally active genes indicate the pronounced role of Rho-mediated termination in Mycobacterium tuberculosis (Mtb). Rho modulates the termination of RNA synthesis for both protein-coding and stable RNA genes in Mtb. Concordantly, the depletion of Rho in mycobacteria impact its growth and enhances the transcription read-through at 3' ends of the transcription units. We demonstrate that MtbRho is catalytically active in the presence of RNA with varied secondary structures. These properties suggest an evolutionary adaptation of Rho as the efficient and preponderant mode of transcription termination in mycobacteria.

Robotic post-chemotherapy retroperitoneal lymph node dissection for testicular cancer: A multicenter collaborative study.

OBJECTIVES: To evaluate the perioperative and oncological/functional outcomes of robotic post-chemotherapy retroperitoneal lymph node dissection for testicular cancer. METHODS AND MATERIALS: In this retrospective study, we included patients who underwent robotic post-chemotherapy retroperitoneal lymph node dissection at 7 academic centers between 2011 and 2021. Patients' characteristics, perioperative findings, as well as oncological and functional outcomes are reviewed. Relationships with the main outcome (90-day complications) were analyzed using multivariable logistic regression. RESULTS: A total of 90 patients with a median (IQR) age of 30 (25-37) years were included. The main primary histologic type was non-seminomatous germ cell tumor (89%). Seven patients (8%) were electively converted to open. Median estimated blood loss, operative time, and length of hospital stay were 150 ml, 5.6 hours, and 2 days, respectively. Final pathology revealed teratoma in 49 (55%), necrosis/fibrosis in 29 (32%), and viable germ cell tumor in 12 (13%) patients. The 90-day complication rate was 16.7%, most of which were low-grade (Clavien-Dindo < III) and managed conservatively. On multivariable analysis, pure seminoma (odds ratio 17.4) and bilateral dissection template (odds ratio 4.2) were independently associated with 90-day complications. No 90-day hospital readmission was recorded. With a median (IQR) follow-up of 16 (4-32) months, 6 (6.7%) patients had disease recurrence and there was 1 cancer-related death. CONCLUSION: With appropriate patient selection at centers with expertise in testicular cancer and minimally invasive surgery, robotic post-chemotherapy retroperitoneal lymph node dissection appears safe and effective, although longer follow-up is warranted.

Metastasis and cancer associated fibroblasts: taking it up a NOTCH.

Metastasis is the least understood aspect of cancer biology. 90% of cancer related deaths occur due extensive metastatic burden in patients. Apart from metastasizing cancer cells, the pro-tumorigenic and pro-metastatic role of the tumor stroma plays a crucial part in this complex process often leading to disease relapse and therapy resistance. Cellular signaling processes play a crucial role in the process of tumorigenesis and metastasis when aberrantly turned on, not just in the cancer cells, but also in the cells of the tumor microenvironment (TME). One of the most conserved pathways includes the Notch signaling pathway that plays a crucial role in the development and progression of many cancers. In addition to its well documented role in cancer cells, recent evidence suggests crucial involvement of Notch signaling in the stroma as well. This review aims to highlight the current findings focusing on the oncogenic role of notch signaling in cancer cells and the TME, with a specific focus on cancer associated fibroblasts (CAFs), which constitute a major part of the tumor stroma and are important for tumor progression. Recent efforts have focused on the development of anti-cancer and anti-metastatic therapies targeting TME. Understanding the importance of Notch signaling in the TME would help identify important drivers for stromal reprogramming, metastasis and importantly, drive future research in the effort to develop TME-targeted therapies utilizing Notch.

Lentiviral interferon: A novel method for gene therapy in bladder cancer.

Interferon alpha (IFNα) gene therapy is emerging as a new treatment option for patients with non-muscle invasive bladder cancer (NMIBC). Adenoviral vectors expressing IFNα have shown clinical efficacy treating bacillus Calmette-Guerin (BCG)-unresponsive bladder cancer (BLCA). However, transient transgene expression and adenoviral immunogenicity may limit therapeutic activity. Lentiviral vectors can achieve stable transgene expression and are less immunogenic. In this study, we evaluated lentiviral vectors expressing murine IFNα (LV-IFNα) and demonstrate IFNα expression by transduced murine BLCA cell lines, bladder urothelium, and within the urine following intravesical instillation. Murine BLCA cell lines (MB49 and UPPL1541) were sensitive to IFN-mediated cell death after LV-IFNα, whereas BBN975 was inherently resistant. Upregulation of interleukin-6 (IL-6) predicted sensitivity to IFN-mediated cell death mediated by caspase signaling, which when inhibited abrogated IFN-mediated cell killing. Intravesical therapy with LV-IFNα/Syn3 in a syngeneic BLCA model significantly improved survival, and molecular analysis of treated tumors revealed upregulation of apoptotic and immune-cell-mediated death pathways. In particular, biomarker discovery analysis identified three clinically actionable targets, PD-L1, epidermal growth factor receptor (EGFR), and ALDHA1A, in murine tumors treated with LV-IFNα/Syn3. Our findings warrant the comparison of adenoviral and LV-IFNα and the study of novel combination strategies with IFNα gene therapy for the BLCA treatment.

Reconfigurable and spectrally switchable perfect absorber based on a phase-change material.

In this paper, we propose a lithography-free spectrally tunable prefect absorber based on an asymmetric Fabry-Perot cavity using Ge2Sb2Te5 (GST), a phase-change material, as the cavity layer. The proposed device shows a maximum absorption of 99.7% at 1550 nm, at a particular angle of incidence and polarization when the phase of GST is in the amorphous state. The absorption spectrum is spectrally switched to longer wavelength when the phase of GST is transformed from amorphous to crystalline. The tuning range is about 866 nm, and the maximum absorption is maintained above 99% in the whole tuning range. The crystallinity ratio of GST is varied by applying voltage pulses of different amplitudes and durations. The electrothermal cosimulations show that the phase change is obtained in the whole GST layer. Furthermore, by reamorphization of GST, the absorption spectrum can be switched back, enabling a reconfigurable perfect absorber. This work shows a viable path toward achieving a tunable perfect absorber covering a 1550 nm communication wavelength window as well as an emerging optical communication window around 2 µm wavelength.

Laser ablation fabrication of ap-NiO/n-Si heterojunction for broadband and self-powered UV-Visible-NIR photodetection.

We report on the optoelectronic characteristics ofp-NiO/n-Si heterojunction photodiode for broadband photodetection, fabricated by depositing ap-type NiO thin film onto a commercialn-type silicon substrate using pulsed laser deposition (PLD) technique. The structural properties of the PLD-grownp-NiO material were analysed by means of x-ray diffraction and x-ray photoelectron spectroscopy, confirming its crystalline nature and revealing the presence of Ni vacancies, respectively. Hall measurements confirmed thep-type semiconducting nature of the NiO thin film having a carrier concentration of 8.4 × 1016cm-3. The current-voltage (I-V) characteristics of thep-NiO/n-Si heterojunction photodevice were investigated under different wavelengths ranging from UV to NIR. The self-bias properties under different illuminations of light were also explored systematically. Under self-bias condition, the photodiode exhibits excellent responsivities of 12.5 mA W-1, 24.6 mA W-1and 30.8 mA W-1with illumination under 365 nm, 485 nm, and 850 nm light, respectively. In addition, the time dependency of the photoresponse of the fabricated photodevice has also been investigated and discussed thoroughly.

Research Progress of Plasmonic Nanostructure-Enhanced Photovoltaic Solar Cells.

Enhancement of the electromagnetic properties of metallic nanostructures constitute an extensive research field related to plasmonics. The latter term is derived from plasmons, which are quanta corresponding to longitudinal waves that are propagating in matter by the collective motion of electrons. Plasmonics are increasingly finding wide application in sensing, microscopy, optical communications, biophotonics, and light trapping enhancement for solar energy conversion. Although the plasmonics field has relatively a short history of development, it has led to substantial advancement in enhancing the absorption of the solar spectrum and charge carrier separation efficiency. Recently, huge developments have been made in understanding the basic parameters and mechanisms governing the application of plasmonics, including the effects of nanoparticles' size, arrangement, and geometry and how all these factors impact the dielectric field in the surrounding medium of the plasmons. This review article emphasizes recent developments, fundamentals, and fabrication techniques for plasmonic nanostructures while investigating their thermal effects and detailing light-trapping enhancement mechanisms. The mismatch effect of the front and back light grating for optimum light trapping is also discussed. Different arrangements of plasmonic nanostructures in photovoltaics for efficiency enhancement, plasmonics' limitations, and modeling performance are also deeply explored.

Metamaterials and Metasurfaces: A Review from the Perspectives of Materials, Mechanisms and Advanced Metadevices.

Throughout human history, the control of light, electricity and heat has evolved to become the cornerstone of various innovations and developments in electrical and electromagnetic technologies. Wireless communications, laser and computer technologies have all been achieved by altering the way light and other energy forms act naturally and how to manage them in a controlled manner. At the nanoscale, to control light and heat, matured nanostructure fabrication techniques have been developed in the last two decades, and a wide range of groundbreaking processes have been achieved. Photonic crystals, nanolithography, plasmonics phenomena and nanoparticle manipulation are the main areas where these techniques have been applied successfully and led to an emergent material sciences branch known as metamaterials. Metamaterials and functional material development strategies are focused on the structures of the matter itself, which has led to unconventional and unique electromagnetic properties through the manipulation of light-and in a more general picture the electromagnetic waves-in widespread manner. Metamaterial's nanostructures have precise shape, geometry, size, direction and arrangement. Such configurations are impacting the electromagnetic light waves to generate novel properties that are difficult or even impossible to obtain with natural materials. This review discusses these metamaterials and metasurfaces from the perspectives of materials, mechanisms and advanced metadevices in depth, with the aim to serve as a solid reference for future works in this exciting and rapidly emerging topic.

Management Trends and Outcomes of Patients Undergoing Radical Cystectomy for Urothelial Carcinoma of the Bladder: Evolution of the University of Southern California Experience over 3,347 Cases.

PURPOSE: There are conflicting reports on outcome trends following radical cystectomy (RC) for bladder cancer. MATERIALS AND METHODS: Evolution of modern bladder cancer management and its impact on outcomes was analyzed using a longitudinal cohort of 3,347 patients who underwent RC at an academic center between 1971 and 2018. Outcomes included recurrence-free survival (RFS) and overall survival (OS). Associations were assessed using univariable and multivariable models. RESULTS: In all, 70.9% of cases underwent open RC in the last decade, although trend for robot-assisted RC rose since 2009. While lymphadenectomy template remained consistent, nodal submission changed to anatomical packets in 2002 with increase in yield (p <0.001). Neoadjuvant chemotherapy (NAC) use increased with time with concomitant decrease in adjuvant chemotherapy; this was notable in the last decade (p <0.001) and coincided with improved pT0N0M0 rate (p=0.013). Median 5-year RFS and OS probabilities were 65% and 55%, respectively. Advanced stage, NAC, delay to RC, lymphovascular invasion and positive margins were associated with worse RFS (all, multivariable p <0.001). RFS remained stable over time (p=0.73) but OS improved (5-year probability, 1990-1999 51%, 2010-2018 62%; p=0.019). Among patients with extravesical and/or node-positive disease, those who received NAC had worse outcomes than those who directly underwent RC (p ≤0.001). CONCLUSIONS: Despite perioperative and surgical advances, and improved pT0N0M0 rates, there has been no overall change in RFS trend following RC, although OS rates have improved. While patients who are downstaged with NAC derive great benefit, our real-world experience highlights the importance of preemptively identifying NAC nonresponders who may have worse post-RC outcomes.

Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer.

Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum. Mechanistically, LRRC15 interacted with ß1-integrin to stimulate activation of focal adhesion kinase (FAK) signaling. As a therapeutic proof of concept, targeting LRRC15 with the specific antibody-drug conjugate ABBV-085 in both early and late metastatic ovarian cancer cell line xenograft models prevented metastatic dissemination, and these results were corroborated in metastatic patient-derived ovarian cancer xenograft models. Furthermore, treatment of 3D-spheroid cultures of LRRC15-positive patient-derived ascites with ABBV-085 reduced cell viability. Overall, these data uncover a role for LRRC15 in promoting ovarian cancer metastasis and suggest a novel and promising therapy to target ovarian cancer metastases.Significance: This study identifies that LRRC15 activates ß1-integrin/FAK signaling to promote ovarian cancer metastasis and shows that the LRRC15-targeted antibody-drug conjugate ABBV-085 suppresses ovarian cancer metastasis in preclinical models.

Structural covariance networks in schizophrenia: A systematic review Part I.

BACKGROUND: Schizophrenia is proposed as a disorder of dysconnectivity. However, examination of complexities of dysconnectivity has been challenging. Structural covariance networks (SCN) provide important insights into the nature of dysconnectivity. This systematic review examines the SCN studies that employed statistical approaches to elucidate covariation of regional morphometric variations. METHODS: A systematic search of literature was conducted for peer-reviewed publications using different keywords and keyword combinations for schizophrenia. Fifty-two studies met the criteria. RESULTS: Early SCN studies began using correlational structure of selected regions. Over the last 3 decades, methodological approaches have grown increasingly sophisticated from examining selected brain regions using correlation tests on small sample sizes to recent approaches that use advanced statistical methods to examine covariance structure of whole-brain parcellations on larger samples. Although the results are not fully consistent across all studies, a pattern of fronto-temporal, fronto-parietal and fronto-thalamic covariation is reported. Attempts to associate SCN alterations with functional connectivity, to differentiate between disease-related and neurodevelopment-related morphometric changes, and to develop "causality-based" models are being reported. Clinical correlation with outcome, psychotic symptoms, neurocognitive and social cognitive performance are also reported. CONCLUSIONS: Application of advanced statistical methods are beginning to provide insights into interesting patterns of regional covariance including correlations with clinical and cognitive data. Although these findings appear similar to morphometric studies, SCNs have the advantage of highlighting topology of these regions and their relationship to the disease and associated variables. Further studies are needed to investigate neurobiological underpinnings of shared covariance, and causal links to clinical domains.

Structural covariance networks in schizophrenia: A systematic review Part II.

BACKGROUND: Examination of structural covariance network (SCN) is gaining prominence among the strategies to delineate dysconnectivity that case-control morphometric comparisons cannot address. Part II of this review extends on the part I of the review that included SCN studies using statistical approaches by examining SCN studies applying graph theoretic approaches to elucidate network properties in schizophrenia. This review also includes SCN studies using graph theoretic or statistical approaches on persons at-risk for schizophrenia. METHODS: A systematic literature search was conducted for peer-reviewed publications using different keywords and keyword combinations for schizophrenia and risk for schizophrenia. Thirteen studies on schizophrenia and five on persons at risk for schizophrenia met the criteria. RESULTS: A variety of findings from over the last 1½ decades showing qualitative and quantitative differences in the global and local structural connectome in schizophrenia are described. These observations include altered hub patterns, disrupted network topology and hierarchical organization of the brain, and impaired connections that may be localized to default mode, executive control, and dorsal attention networks. Some of these connectomic alterations were observed in persons at-risk for schizophrenia before the onset of the illness. CONCLUSIONS: Observed disruptions may reduce network efficiency and capacity to integrate information. Further, global connectomic changes were not schizophrenia-specific but local network changes were. Existing studies have used different atlases for brain parcellation, examined different morphometric features, and patients at different stages of illness making it difficult to conduct meta-analysis. Future studies should harmonize such methodological differences to facilitate meta-analysis and also elucidate causal underpinnings of dysconnectivity.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.