Assessment of Patient-Derived Xenograft Growth and Antitumor Activity: The NCI PDXNet Consensus Recommendations.

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.

Association between Preoperative C-Reactive Protein-to-Albumin Ratio and Mortality after Plastic and Reconstructive Surgery.

Background: Prognostic markers have not been extensively studied in plastic and reconstructive surgery. Objective: We aimed to evaluate the prognostic value of preoperative C-reactive protein (CRP)-to-albumin ratio (CAR) in plastic and reconstructive surgery and to compare it with the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS). Methods: From January 2011 to July 2019, we identified 2519 consecutive adult patients who were undergoing plastic and reconstructive surgery with available preoperative CRP and albumin levels. The receiver operating characteristic (ROC) curve was generated to evaluate predictability and estimate the threshold. The patients were divided according to this threshold, and the risk was compared. The primary outcome was one-year mortality, and the overall mortality was also analyzed. Results: The one-year mortality was 4.9%. The CAR showed an area under the ROC curve of 0.803, which was higher than those of NLR, PLR, and mGPS. According to the estimated threshold of 1.05, the patients were divided into two groups; 1585 (62.9%) were placed in the low group, and 934 (37.1%) were placed in the high group. After inverse probability weighting, the mortality rate during the first year after plastic and reconstructive surgery was significantly increased in the high group (1.3% vs. 10.9%; hazard ratio, 2.88; 95% confidence interval, 2.17-3.83; p < 0.001). Conclusions: In this study, high CAR was significantly associated with one-year mortality of patients after plastic and reconstructive surgery. Further studies are needed on prognostic markers in plastic and reconstructive surgery.

Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

Moderate intensity walking exercises reduce the body mass index and vascular inflammatory factors in postmenopausal women with obesity: a randomized controlled trial.

Postmenopause, the secretion of female hormones changes, causing excessive fat accumulation in the body and leading to chronic inflammation, which increases the incidence of cardiovascular diseases (CVD). Walking is an easily accessible daily exercise and effective non-pharmacological treatment for reducing obesity and the incidence of CVD. The aim of this study was to investigate the effect of moderate intensity walking exercises on body composition, vascular inflammatory factors, and vascular endothelial growth factor (VEGF) in postmenopausal women with obesity. Twenty-six older postmenopausal women with obesity (ages 68-72) were randomly assigned to control (n = 12, BMI 26.06 ± 1.37) or exercise (n = 14, BMI 26.04 ± 1.94) groups. Following a 12-week moderate intensity walking exercise program, we measured the participants' body composition with an InBody S10 analyzer and assessed blood sera using enzyme-linked immunosorbent assays. There was a significant clustering by weight (p < 0.01), body mass index (p < 0.01), percentage body fat (p < 0.001), high-sensitivity C-reactive protein (p < 0.05), interleukin-6, and tumor necrosis factor-α (p < 0.05) being significantly decreased in the exercise group. Although VEGF levels did not change significantly, a tendency to increase was observed in participants that exercised. Our results indicate that walking exercise may help prevent CVD in postmenopausal women with obesity by reducing obesity and vascular inflammatory factors.

Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer.

Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib's efficacy in breast cancer models. Nine breast cancer patient-derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro. FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2-amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%-2.6% and 1.5%-2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

FAM64A aggravates proliferation, invasion, lipid droplet formation, and chemoresistance in gastric cancer: A biomarker for aggressiveness and a gene therapy target.

FAM64A is a mitogen-induced regulator of the metaphase and anaphase transition. Here, we found that FAM64A messenger RNA (mRNA) and protein expression levels were higher in gastric cancer tissue than in normal mucosa (p < .05). FAM64A methylation was negatively correlated with FAM64A mRNA expression (p < .05). The differentially expressed genes of FAM64A were mainly involved in digestion, potassium transporting or exchanging ATPase, contractile fibers, endopeptidase, and pancreatic secretion (p < .05). The FAM64A-related genes were principally categorized into ubiquitin-mediated proteolysis, cell cycle, chromosome segregation and mitosis, microtubule binding and organization, metabolism of amino acids, cytokine receptors, lipid droplet, central nervous system, and collagen trimer (p < .05). FAM64A protein expression was lower in normal gastric mucosa than intestinal metaplasia, adenoma, and primary cancer (p < .05), negatively correlated with older age, T stage, lymphatic and venous invasion, tumor, node, metastasis stage, and dedifferentiation (p < .05), and associated with a favorable overall survival of gastric cancer patients. FAM64A overexpression promoted proliferation, antiapoptosis, migration, invasion, and epithelial-mesenchymal transition via the EGFR/Akt/mTOR/NF-κB, while the opposite effect was observed for FAM64A knockdown. FAM64A also induced chemoresistance directly or indirectly through lipid droplet formation via ING5. These results suggested that upregulation of FAM64A expression might induce aggressive phenotypes, leading to gastric carcinogenesis and its subsequent progression. Thus, FAM64A could be regarded as a prognosis biomarker and a target for gene therapy.

Elevated risk of cervical cancer in elderly women with incident ulcerative colitis in South Korea.

The association between ulcerative colitis (UC) and uterine cervical cancer is still unclear. To investigate cervical cancer risk in South Korean women with UC, we analyzed the Korean National Health Insurance claims data. UC was defined using both ICD-10 codes and UC-specific prescriptions. We analyzed incident cases of UC diagnosed between 2006 and 2015. Age-matched women without UC (control group) were randomly selected from the general population (1:3 ratio). Hazard ratios were calculated using multivariate Cox proportional hazard regression, and the event was defined as occurrence of cervical cancer. A total of 12,632 women with UC and 36,797 women without UC were enrolled. The incidence of cervical cancer was 38.8 per 100,000 women per year in UC patients and 25.7 per 100,000 women per year in controls, respectively. The adjusted HR for cervical cancer was 1.56 (95% CI 0.97-2.50) in the UC group with reference to the control group. When stratified by age, the adjusted HR for cervical cancer was 3.65 (95% CI 1.54-8.66) in elderly UC patients (≥ 60 years) compared to elderly control group (≥ 60 years). Within UC patients, increased age (≥ 40 years) and low socioeconomic status were associated with an increased risk of cervical cancer. The incidence of cervical cancer was found to be higher among elderly patients (≥ 60 years) with newly diagnosed UC in South Korea, compared to age-matched controls. Therefore, regular cervical cancer screening is recommended for elderly patients who have recently been diagnosed with UC.

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib.

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

Association between changes in having of cancer patients in the family and depression: A longitudinal panel study.

BACKGROUND: Cancer diagnosis can cause considerable stress among patients and their families. Both may experience clinical depression and severe anxiety. Therefore, this study investigated the association between the occurrence of cancer patients in the family and the depression among family members. METHODS: Data from the Korean Longitudinal Study of Aging (2006-2020) were used. A total of 6251 participants who completed the short-form Center for Epidemiologic Studies Depression Scale (CESD-10-D) questionnaire were included. General estimating equations were used to assess the temporal effects of changes on depression in the presence of cancer patients in the family. RESULTS: Having cancer patients in the family was associated with a high risk of depression among both men and women (men, Odds Ratio (OR):1.78, 95 % Confidence Intervals (CI) 1.13-2.79; women, OR:1.53, 95 % CI 1.06-2.22). Depressive symptoms were particularly high in women, especially when cancer symptoms were more severe than previous surveys (OR: 2.48, 95 % CI 1.18-5.20). LIMITATIONS: First, non-responders were excluded but this could be affected by underestimation bias. Second, depression was defined as the CESD-10-D score, and the biological risk factors of depression could not be identified because of survey-based database. Third, due to the retrospective design study, confirming the causal relationship clearly is difficult. Finally, residual scheming effects of unmeasured variables could not be eliminated. CONCLUSION: Our findings support efforts to diagnose and manage depression in the families of cancer patients. Accordingly, healthcare services and supportive interventions to reduce the psychological factors of cancer patients' families are needed.

Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma.

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation. STATEMENT OF SIGNIFICANCE: Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.

A unified mediation analysis framework for integrative cancer proteogenomics with clinical outcomes.

MOTIVATION: Multilevel molecular profiling of tumors and the integrative analysis with clinical outcomes have enabled a deeper characterization of cancer treatment. Mediation analysis has emerged as a promising statistical tool to identify and quantify the intermediate mechanisms by which a gene affects an outcome. However, existing methods lack a unified approach to handle various types of outcome variables, making them unsuitable for high-throughput molecular profiling data with highly interconnected variables. RESULTS: We develop a general mediation analysis framework for proteogenomic data that include multiple exposures, multivariate mediators on various scales of effects as appropriate for continuous, binary and survival outcomes. Our estimation method avoids imposing constraints on model parameters such as the rare disease assumption, while accommodating multiple exposures and high-dimensional mediators. We compare our approach to other methods in extensive simulation studies at a range of sample sizes, disease prevalence and number of false mediators. Using kidney renal clear cell carcinoma proteogenomic data, we identify genes that are mediated by proteins and the underlying mechanisms on various survival outcomes that capture short- and long-term disease-specific clinical characteristics. AVAILABILITY AND IMPLEMENTATION: Software is made available in an R package (https://github.com/longjp/mediateR). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of physical activity levels on blood lipids, insulin resistance, and adipokines in children with obesity.

PURPOSE: Our study was performed to observe children with obesity by using accelerometers and identify their differences in blood lipid levels, insulin resistance, and adipokines based on their physical activity levels. METHODS: 197 obese children were classified into three groups based on their physical activity levels over a period of 7 days, using the average counts per minute: Sedentary Time (ST), Light Physical Activity (LPA), and Moderate to Vigorous Intensity Physical Activity (MVPA). Blood lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were analyzed. Insulin resistance was assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) formula. Adipokines, including leptin and resistin, were measured. Our results were obtained through one-way analysis of variance was employed, with Scheffe post-hoc analysis. The statistical significance level was set at p < 0.05 for all analyses. RESULTS: Results showed that the levels of blood lipids (TG: p<0.001, TC: p<0.01, LDL-C: p<0.001, HDL-C: p< 0.05) and adipokines (Leptin, Resistin: p<0.01) of children who had obesity and maintained moderate to vigorous physical activity were healthier than those who engaged in ST or LPA. Specifically, children with obesity engaging in MVPA demonstrated blood lipid and adipokine levels that were normal or close to normal. However, no significant differences in insulin resistance were observed in all groups. CONCLUSION: In summary, encouraging moderate to vigorous physical activity in children with obesity could help improve obesity indicators, such as blood lipids and adipokines.

Pharmacophore-Oriented Identification of Potential Leads as CCR5 Inhibitors to Block HIV Cellular Entry.

Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients. This indicates that there is a need for novel CCR5 antagonists. Keeping this in mind, the present study was designed. The active CCR5 inhibitors with known IC50 value were selected from the literature and utilized to develop a ligand-based common feature pharmacophore model. The validated pharmacophore model was further used for virtual screening of drug-like databases obtained from the Asinex, Specs, InterBioScreen, and Eximed chemical libraries. Utilizing computational methods such as molecular docking studies, molecular dynamics simulations, and binding free energy calculation, the binding mechanism of selected inhibitors was established. The identified Hits not only showed better binding energy when compared to Maraviroc, but also formed stable interactions with the key residues and showed stable behavior throughout the 100 ns MD simulation. Our findings suggest that Hit1 and Hit2 may be potential candidates for CCR5 inhibition, and, therefore, can be considered for further CCR5 inhibition programs.

Association between postoperative acute kidney injury and mortality after plastic and reconstructive surgery.

Acute kidney injury (AKI) is a common postoperative disorder that is associated with considerable morbidity and mortality. Although the role of AKI as an independent risk factor for mortality has been well characterized in major surgeries, its effect on postoperative outcomes in plastic and reconstructive surgery has not been evaluated. This study explored the association between postoperative AKI and mortality in patients undergoing plastic and reconstructive surgery. Consecutive adult patients who underwent plastic and reconstructive surgery without end-stage renal disease (n = 7059) at our institution from January 2011 to July 2019 were identified. The patients were divided into two groups according to occurrence of postoperative AKI: 7000 patients (99.2%) in the no AKI group and 59 patients (0.8%) in the AKI group. The primary outcome was mortality during the first year, and overall mortality and 30-days mortality were also compared. After inverse probability weighting, mortality during the first year after plastic and reconstructive surgery was significantly increased in the AKI group (1.9% vs. 18.6%; hazard ratio, 6.69; 95% confidence interval, 2.65-16.85; p < 0.001). In this study, overall and 30-day mortalities were shown to be higher in the AKI group, and further studies are needed on postoperative AKI in plastic and reconstructive surgery.

The effects of REG4 expression on chemoresistance of ovarian cancer.

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENTWhat is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway.What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment.What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors.

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.

CombPDX: a unified statistical framework for evaluating drug synergism in patient-derived xenografts.

Anticancer combination therapy has been developed to increase efficacy by enhancing synergy. Patient-derived xenografts (PDXs) have emerged as reliable preclinical models to develop effective treatments in translational cancer research. However, most PDX combination study designs focus on single dose levels, and dose-response surface models are not appropriate for testing synergism. We propose a comprehensive statistical framework to assess joint action of drug combinations from PDX tumor growth curve data. We provide various metrics and robust statistical inference procedures that locally (at a fixed time) and globally (across time) access combination effects under classical drug interaction models. Integrating genomic and pharmacological profiles in non-small-cell lung cancer (NSCLC), we have shown the utilities of combPDX in discovering effective therapeutic combinations and relevant biological mechanisms. We provide an interactive web server, combPDX ( https://licaih.shinyapps.io/CombPDX/ ), to analyze PDX tumor growth curve data and perform power analyses.

Comparison of Clinical Symptoms and Neurophysiological Findings in Patients With Chemotherapy Induced Peripheral Neuropathy.

Introduction: Taxanes are associated with a distal sensory neuropathy, significantly affecting cancer survivor quality of life. However, chemotherapy-induced peripheral neuropathy (CIPN) assessments are primarily based on clinical symptoms rather than objective neurophysiologic findings. Therefore, we investigated neurophysiologic changes in symptomatic subjects, comparing them with symptom severity. Materials and Methods: Medical charts of 111 subjects who were referred for CIPN diagnosis after chemotherapy for breast or ovarian cancer between May 1, 2016, and December 31, 2019, were retrospectively reviewed. Demographics, anthropometric parameters, and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale data were collected. The nerve conduction study (NCS) results, including sensory nerve action potentials recorded from sural nerves, were analyzed relative to clinical symptoms. To optimize follow-up (FU) NCS diagnostic sensitivity, relative references of FU sural amplitude reductions to >30% and an absolute reference <10 µV were used. Results: Eighty-eight female patients met the criteria, and 20 underwent FU NCS. Baseline and FU sural amplitudes showed significant positive correlation with respective LANSS scores (p < 0.01). FU sural amplitude was significantly lower than the initial result (p < 0.05). The FU LANSS score was not different from the initial score. Initial NCS sensitivity and specificity for clinically suspected CIPN diagnoses with LANSS were 69.7 and 47.3%, respectively. All 20 subjects with FU evaluation were clinically compatible with CIPN (LANSS >12) at initial and FU assessments. Among them, only six (30.0%) had abnormal sural amplitudes (<10µV for ≤50 s, <3 µV for 60 s, <1 µV for 70 s) in the initial NCS. In the FU NCS, sural amplitude became abnormal in five additional subjects. Between the initial and FU NCS, sural amplitude was reduced by > 30% in eight subjects (40.0%). NCS sensitivity increased to 65.0% when including either abnormal sural amplitudes or a > 30% reduction in sural amplitude in FU studies. Conclusions: Although clinical symptoms and NCS results were positively correlated, a single NCS point had limited value for suspected CIPN electrophysiological diagnoses. Serial NCS during chemotherapy might help assess the degree of chemotherapy-induced nerve damage, attain evidence of CIPN prior to symptom aggravation, and monitor the progression of CIPN. Further study is needed to find specific relative references for variable patient factors to increase the sensitivity of electrophysiological studies of clinically suspected CIPN.

Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes.

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.

TUSC2 immunogene enhances efficacy of chemo-immuno combination on KRAS/LKB1 mutant NSCLC in humanized mouse model.

KRAS/LKB1 (STK11) NSCLC metastatic tumors are intrinsically resistant to anti-PD-1 or PD-L1 immunotherapy. In this study, we use a humanized mouse model to show that while carboplatin plus pembrolizumab reduce tumor growth moderately and transiently, the addition of the tumor suppressor gene TUSC2, delivered systemically in nanovesicles, to this combination, eradicates tumors in the majority of animals. Immunoprofiling of the tumor microenvironment shows the addition of TUSC2 mediates: (a) significant infiltration of reconstituted human functional cytotoxic T cells, natural killer cells, and dendritic cells; (b) induction of antigen-specific T cell responses; (c) enrichment of functional central and memory effector T cells; and (d) decreased levels of PD-1+ T cells, myeloid-derived suppressor cells, Tregs, and M2 tumor associated macrophages. Depletion studies show the presence of functional central and memory effector T cells are required for the efficacy. TUSC2 sensitizes KRAS/LKB1 tumors to carboplatin plus pembrolizumab through modulation of the immune contexture towards a pro-immune tumor microenvironment.