Lean body mass in living kidney donors impacts postoperative renal function.

PURPOSE: A living donor kidney transplant is the optimal treatment for chronic renal impairment. Our objective is to assess if lean skeletal muscle mass and donor factors such as body mass index, hypertension, and age impact on renal function following donor nephrectomy. METHODS: Potential donors undergo CT angiography as part of their work-up in our institution. Using dedicated software (Horos®), standardized skeletal muscle area measured at the L3 vertebrae was calculated. When corrected for height, skeletal muscle index can be derived. Skeletal muscle mass index below predefined levels was classified as sarcopenic. The correlation of CT-derived skeletal muscle index and postoperative renal function at 12 months was assessed. Co-variables including donor gender, age, body mass index (BMI), and presence of pre-op hypertension were also assessed for their impact on postoperative renal function. RESULTS: 275 patients who underwent living donor nephrectomy over 10 years were included. Baseline pre-donation glomerular filtration rate (GFR) and renal function at one year post-op were similar between genders. 29% (n = 82) of patients met the criteria for CT-derived sarcopenia. Sarcopenic patients were more likely to have a higher GFR at one year post-op (69.3 vs 63.9 mL/min/1.73 m2, p < 0.001). The main factors impacting better renal function at one year were the presence of sarcopenia and younger age at donation. CONCLUSION: When selecting donors, this study highlights that patients with low skeletal mass are unlikely to underperform in terms of recovery of their renal function postoperatively at one year when compared to patients with normal muscle mass and should not be a barrier to kidney donation.

Civilian Ballistic Injuries to the Atlantoaxial Spine: A Single Institution Case Series.

STUDY DESIGN: Retrospective case series. OBJECTIVE: Describe the injury characteristics of ballistic fractures involving the atlantoaxial spine. SUMMARY OF BACKGROUND DATA: Civilian gunshot wounds to the spine are an increasingly common injury in the United States. Civilian studies have focused on ballistic injuries to the entire spine as opposed to a region-specific fashion. Only a single 10-patient case series investigating ballistic fractures to the upper cervical spine (C1 and C2) exists, leaving a large gap in the understanding of this injury complex. METHODS: A retrospective chart review was performed. Extracted data included patient demographics, neurological status on presentation, fracture morphology, assessment of stability, other associated injuries, and surgical procedures performed. Proportional analysis was performed to characterize the fractures and their associated neurological injuries. RESULTS: Thirty-six patients were identified, with 86% being male with an average patient age of 30.0 ± 10.36 years (mean ± SD). Fracture morphology was characterized using proportional analysis. Initial neurological exams were either ASIA A or ASIA E, without any incomplete injuries noted. Patients who sustained a transcanal injury did not show any neurological improvement. The initial in-hospital mortality rate was 5.6%, with a 1-year mortality rate of 8.3%. There is a high incidence of associated vascular injury (66%) and mandible fracture (33%). CONCLUSIONS: Ballistic penetrating trauma to the atlantoaxial spine often results in complex injury patterns necessitating multidisciplinary care with high rates of morbidity and mortality. If neurological deficits are present initially, they are often complete. Two thirds of patients sustained an associated vascular injury, which should be screened for with CT angiography.

Functional genomic screens with death rate analyses reveal mechanisms of drug action.

A common approach for understanding how drugs induce their therapeutic effects is to identify the genetic determinants of drug sensitivity. Because 'chemo-genetic profiles' are performed in a pooled format, inference of gene function is subject to several confounding influences related to variation in growth rates between clones. In this study, we developed Method for Evaluating Death Using a Simulation-assisted Approach (MEDUSA), which uses time-resolved measurements, along with model-driven constraints, to reveal the combination of growth and death rates that generated the observed drug response. MEDUSA is uniquely effective at identifying death regulatory genes. We apply MEDUSA to characterize DNA damage-induced lethality in the presence and absence of p53. Loss of p53 switches the mechanism of DNA damage-induced death from apoptosis to a non-apoptotic death that requires high respiration. These findings demonstrate the utility of MEDUSA both for determining the genetic dependencies of lethality and for revealing opportunities to potentiate chemo-efficacy in a cancer-specific manner.

The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities.

The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (ß-catenin dependent) and non-canonical (ß-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.

Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

Dynamic regulation of hepatic lipid metabolism by torsinA and its activators.

Depletion of torsinA from hepatocytes leads to reduced liver triglyceride secretion and marked hepatic steatosis. TorsinA is an atypical ATPase that lacks intrinsic activity unless it is bound to its activator, lamina-associated polypeptide 1 (LAP1) or luminal domain-like LAP1 (LULL1). We previously demonstrated that depletion of LAP1 from hepatocytes has more modest effects on liver triglyceride secretion and steatosis development than depletion of torsinA. We now show that depletion of LULL1 alone does not significantly decrease triglyceride secretion or cause steatosis. However, simultaneous depletion of both LAP1 and LULL1 leads to defective triglyceride secretion and marked steatosis similar to that observed with depletion of torsinA. Depletion of both LAP1 and torsinA from hepatocytes generated phenotypes similar to those observed with only torsinA depletion, implying that the 2 proteins act in the same pathway in liver lipid metabolism. Our results demonstrate that torsinA and its activators dynamically regulate hepatic lipid metabolism.

Erythrophagocytosis is not a reproducible finding in liver biopsies, and is not associated with clinical diagnosis of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was .08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy.

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib's off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.

Unravelling interobserver variability in gastrointestinal glandular neoplasia: a contemporary study of US and Korean pathologists.

AIMS: Interobserver variability in the assessment of gastric neoplasia biopsies between most Western and Eastern (predominantly represented by Japanese in the literature) pathologists has been documented. It is unknown if such variability exists between the US and Korean pathologists in the current era. METHODS: Ten gastrointestinal (GI) pathologists from the USA (n=5) and South Korea (n=5) evaluated 100 scanned images of gastric (n=50) and colorectal (n=50) neoplasia biopsies and answered multiple questionnaires. Consensus was defined as the answer chosen by the majority. Cohen's (κc) and Fleiss' kappa (κf) values were calculated between the consensus of the two groups and among the raters, respectively. RESULTS: Both groups reached a consensus in the majority of cases (74%-100%) with slight to perfect intergroup (κc=0.049-1.000) and no to substantial intragroup (κf=-0.083 to 0.660) agreements. For gastric neoplasia, Korean pathologists relied heavily on cytoarchitectural atypia, whereas the US pathologists focused on stromal invasion when diagnosing adenocarcinoma. For colorectal neoplasia, the Korean pathologists identified concurrent intramucosal carcinoma when diagnosing invasive adenocarcinoma, while the presence of desmoplasia was a prerequisite for the diagnosis of invasive adenocarcinoma for the US pathologists. CONCLUSIONS: For GI neoplasia biopsy interpretation, the diagnostic approach of Korean pathologists is similar to that of Eastern/Japanese pathologists. Consensus outperformed kappa statistics in capturing the magnitude of inter-rater and intergroup reliability, highlighting the potential benefit of consensus meetings to decrease the gap between Western and Eastern diagnostic approaches.

Functional interaction of torsinA and its activators in liver lipid metabolism.

TorsinA is an atypical ATPase that lacks intrinsic activity unless it is bound to its activators lamina-associated polypeptide 1 (LAP1) in the perinuclear space or luminal domain-like LAP1 (LULL1) throughout the endoplasmic reticulum. However, the interaction of torsinA with LAP1 and LULL1 has not yet been shown to modulate a defined physiological process in mammals in vivo . We previously demonstrated that depletion of torsinA from mouse hepatocytes leads to reduced liver triglyceride secretion and marked steatosis, whereas depletion of LAP1 had more modest similar effects. We now show that depletion of LULL1 alone does not significantly decrease liver triglyceride secretion or cause steatosis. However, simultaneous depletion of both LAP1 and LULL1 from hepatocytes leads to defective triglyceride secretion and marked steatosis similar to that observed with depletion of torsinA. Our results demonstrate that torsinA and its activators dynamically regulate a physiological process in mammals in vivo .

Mitochondria of lung venular capillaries mediate lung-liver cross talk in pneumonia.

Failure of the lung's endothelial barrier underlies lung injury, which causes the high mortality acute respiratory distress syndrome (ARDS). Multiple organ failure predisposes to the mortality, but mechanisms are poorly understood. Here, we show that mitochondrial uncoupling protein 2 (UCP2), a component of the mitochondrial inner membrane, plays a role in the barrier failure. Subsequent lung-liver cross talk mediated by neutrophil activation causes liver congestion. We intranasally instilled lipopolysaccharide (LPS). Then, we viewed the lung endothelium by real-time confocal imaging of the isolated, blood-perfused mouse lung. LPS caused alveolar-capillary transfer of reactive oxygen species and mitochondrial depolarization in lung venular capillaries. The mitochondrial depolarization was inhibited by transfection of alveolar Catalase and vascular knockdown of UCP2. LPS instillation caused lung injury as indicated by increases in bronchoalveolar lavage (BAL) protein content and extravascular lung water. LPS or Pseudomonas aeruginosa instillation also caused liver congestion, quantified by liver hemoglobin and plasma aspartate aminotransferase (AST) increases. Genetic inhibition of vascular UCP2 prevented both lung injury and liver congestion. Antibody-mediated neutrophil depletion blocked the liver responses, but not lung injury. Knockdown of lung vascular UCP2 mitigated P. aeruginosa-induced mortality. Together, these data suggest a mechanism in which bacterial pneumonia induces oxidative signaling to lung venular capillaries, known sites of inflammatory signaling in the lung microvasculature, depolarizing venular mitochondria. Successive activation of neutrophils induces liver congestion. We conclude that oxidant-induced UCP2 expression in lung venular capillaries causes a mechanistic sequence leading to liver congestion and mortality. Lung vascular UCP2 may present a therapeutic target in ARDS.NEW & NOTEWORTHY We report that mitochondrial injury in lung venular capillaries underlies barrier failure in pneumonia, and venular capillary uncoupling protein 2 (UCP2) causes neutrophil-mediated liver congestion. Using in situ imaging, we found that epithelial-endothelial transfer of H2O2 activates UCP2, depolarizing mitochondria in venular capillaries. The conceptual advance from our findings is that mitochondrial depolarization in lung capillaries mediates liver cross talk through circulating neutrophils. Pharmacologic blockade of UCP2 could be a therapeutic strategy for lung injury.

A review of liver fibrosis and cirrhosis regression.

Cirrhosis has traditionally been considered an irreversible process of end-stage liver disease. With new treatments for chronic liver disease, there is regression of fibrosis and cirrhosis, improvement in clinical parameters (i.e. liver function and hemodynamic markers, hepatic venous pressure gradient), and survival rates, demonstrating that fibrosis and fibrolysis are a dynamic process moving in two directions. Microscopically, hepatocytes push into thinning fibrous septa with eventual perforation leaving behind delicate periportal spikes in the portal tracts and loss of portal veins. Obliterated portal veins during progressive fibrosis and cirrhosis due to parenchymal extinction, vascular remodeling and thrombosis often leave behind a bile duct and hepatic artery within the portal tract. Traditional staging classification systems focused on a linear, progressive process; however, the Beijing classification system incorporates both the bidirectional nature for the progression and regression of fibrosis. However, even with regression, vascular lesions/remodeling, parenchymal extinction and a cumulative mutational burden place patients at an increased risk for developing hepatocellular carcinoma and should continue to undergo active clinical surveillance. It is more appropriate to consider cirrhosis as another stage in the evolution of chronic liver disease as a bidirectional process rather than an end-stage, irreversible state.

Radioembolization for Treatment of Hepatocellular Carcinoma: Current Evidence and Patterns of Utilization.

Primary liver malignancy, of which hepatocellular carcinoma (HCC) is the most common type, is the second most common cause of death due to cancer worldwide. Given the historically poor prognosis of liver cancer, there has been major research on its treatment options, with significant advancements over the last decade. Transarterial radioembolization (TARE) is a locoregional treatment option for HCC that involves transarterial delivery of the ß-emitter yttrium-90 via resin or glass microspheres to arterialized tumor vasculature, delivering a tumoricidal dose to the tumor. The recent 2022 update of the Barcelona Clinic Liver Cancer (BCLC) treatment algorithm features a more prominent role for locoregional treatment, including the incorporation of radioembolization for very-early-stage (BCLC-0) and early-stage (BCLC-A) diseases. This review provides a contemporary summary of the evolving role of TARE in treatment of HCC in light of recent and upcoming trials.

CT imaging for occult malignancy in patients with unprovoked venous thromboembolism (VTE) in a tertiary centre: is it worthwhile?

BACKGROUND: Investigating patients with unprovoked venous thromboembolism (uVTE) for occult malignancy can prove a diagnostic dilemma and imaging is often used extensively in this patient group. AIMS: The primary objective of this study was to determine the incidence of malignancy on CT and other imaging over a 10-year period. A secondary objective was to evaluate the role of laboratory and other non-imaging tests performed. METHODS: A retrospective key word search of our hospital's imaging system was performed to identify patients with unprovoked DVT/PE over the last 10 years. All imaging, histology, endoscopy, laboratory tests, and clinical follow-up over 2 years were analysed. Patients with provoked VTE were excluded. RESULTS: 150 patients had uVTE. 9 patients were diagnosed with occult malignancy by different investigations on index hospital admission (3 patients) or subsequently on clinical follow-up (6 patients). Mean age of patients was 62 years. 116 patients had CT body imaging. The incidence of malignancy diagnosed by initial CT imaging was 1.7% with a sensitivity of 22%, specificity 87%, and PPV 12.5%. Overall incidence of malignancy identified by imaging alone during the index hospital admission was 2%. Total incidence of malignancy including index admission and follow-up was 6%. Median time to cancer diagnosis was 12 months. CONCLUSION: CT imaging had a low yield for diagnosing malignancy. Extensive imaging strategies increase cost and radiation exposure without improving mortality. Clinical follow-up, history taking, and physical examination guiding appropriate investigations remain the best tool for unmasking occult malignancy in patients with uVTE.

An 8-year, single-centre experience of primary image-guided insertion of 'button' gastrostomy catheters: Technical and clinical results.

INTRODUCTION: 'Button' gastrostomy insertion is traditionally a two-step procedure with an initial longer gastrostomy tube inserted followed by placement of the shorter 'button' gastrostomy in 6 weeks when the track is mature. The aim of this study is to assess whether the placement of a Button gastrostomy de novo is a safe and effective method of radiologically inserted gastrostomy (RIG) insertion. METHODS: Using our Picture Archive and Communication System (PACS) and electronic patient charts we identified all patients who underwent primary 'button' gastrostomy over an 8-year period with at least a 1-year follow-up period. We evaluated technical success rate, indications for insertion, major and minor complications, 30-day mortality and the number of exchanges performed. RESULTS: Overall, 482 patients underwent a primary button RIG insertion during this period with an overall success rate of 97.1%. Indications for RIG insertion included neurological and neurosurgical disorders 236 (48.9%), head and neck malignancy 182 (37.8%), oesophageal malignancy 27 (5.6%) and other indications in 37 (7.7%). The mean age was 59.55 years (range 18-88 years) with 290 men (60.2%) and 192 women (39.8%). Major complications were recorded in 0.8% and minor complications in 1.7%. A 30-day mortality of 1% was identified (five patients), mortality was directly related to the RIG insertion in one patient (0.2%). A total of 65 exchanges/replacements took place over this period of time, with 33 (50.1%) due to 'inadvertent removal'. CONCLUSION: Primary button RIG insertion is a procedure that has a high success rate and low morbidity and mortality. We believe it is a safe and effective alternative to deliver enteral nutrition.

Agent-Based Models Help Interpret Patterns of Clinical Drug Resistance by Contextualizing Competition Between Distinct Drug Failure Modes.

Introduction: Modern targeted cancer therapies are carefully crafted small molecules. These exquisite technologies exhibit an astonishing diversity of observed failure modes (drug resistance mechanisms) in the clinic. This diversity is surprising because back of the envelope calculations and classic modeling results in evolutionary dynamics suggest that the diversity in the modes of clinical drug resistance should be considerably smaller than what is observed. These same calculations suggest that the outgrowth of strong pre-existing genetic resistance mutations within a tumor should be ubiquitous. Yet, clinically relevant drug resistance occurs in the absence of obvious resistance conferring genetic alterations. Quantitatively, understanding the underlying biological mechanisms of failure mode diversity may improve the next generation of targeted anticancer therapies. It also provides insights into how intratumoral heterogeneity might shape interpatient diversity during clinical relapse. Materials and Methods: We employed spatial agent-based models to explore regimes where spatial constraints enable wild type cells (that encounter beneficial microenvironments) to compete against genetically resistant subclones in the presence of therapy. In order to parameterize a model of microenvironmental resistance, BT20 cells were cultured in the presence and absence of fibroblasts from 16 different tissues. The degree of resistance conferred by cancer associated fibroblasts in the tumor microenvironment was quantified by treating mono- and co-cultures with letrozole and then measuring the death rates. Results and Discussion: Our simulations indicate that, even when a mutation is more drug resistant, its outgrowth can be delayed by abundant, low magnitude microenvironmental resistance across large regions of a tumor that lack genetic resistance. These observations hold for different modes of microenvironmental resistance, including juxtacrine signaling, soluble secreted factors, and remodeled ECM. This result helps to explain the remarkable diversity of resistance mechanisms observed in solid tumors, which subverts the presumption that the failure mode that causes the quantitatively fastest growth in the presence of drug should occur most often in the clinic. Conclusion: Our model results demonstrate that spatial effects can interact with low magnitude of resistance microenvironmental effects to successfully compete against genetic resistance that is orders of magnitude larger. Clinical outcomes of solid tumors are intrinsically connected to their spatial structure, and the tractability of spatial agent-based models like the ones presented here enable us to understand this relationship more completely.

Rates of Future Lumbar Fusion in Patients with Cauda Equina Syndrome Treated With Decompression.

INTRODUCTION: The long-term risk of conversion to lumbar fusion is ill-defined for patients with cauda equina syndrome (CES) treated with decompression. This study aimed to identify the rates of fusion in patients with CES and compare those rates with a matched lumbar spinal stenosis (LSS) group. METHODS: Patients with CES who underwent decompression were identified in a national database and matched to control patients with LSS. The rates of conversion to fusion were identified and compared. Multivariate logistic regression analysis identified independently associated risk factors. A subanalysis was conducted after stratifying by timing between CES diagnosis and decompression. RESULTS: The rate of lumbar fusion in the CES cohort was 3.6% after 1 year, 6.7% after 3 years, and 7.8% after 5 years, significantly higher than the LSS control group at all time points (1 year: 1.6%, P = 0.001; 3 years: 3.0%, P < 0.001; 5 years: 3.8%, P < 0.001). CES was independently associated with increased risk of conversion to fusion (odds ratio: 2.13; 95% confidence interval: 1.56 to 2.97; P < 0.001). Surgical timing was not associated with risk of conversion to fusion. CONCLUSIONS: After 5 years, 7.8% of patients with CES underwent fusion, a markedly higher rate compared with patients with LSS. Counseling patients with CES on this increased risk of future surgery is important for patient education and satisfaction.

Materials-driven approaches to understand extrinsic drug resistance in cancer.

Metastatic cancer has a poor prognosis, because it is broadly disseminated and associated with both intrinsic and acquired drug resistance. Critical unmet needs in effectively killing drug resistant cancer cells include overcoming the drug desensitization characteristics of some metastatic cancers/lesions, and tailoring therapeutic regimens to both the tumor microenvironment and the genetic profiles of the resident cancer cells. Bioengineers and materials scientists are developing technologies to determine how metastatic sites exclude therapies, and how extracellular factors (including cells, proteins, metabolites, extracellular matrix, and abiotic factors) at metastatic sites significantly affect drug pharmacodynamics. Two looming challenges are determining which feature, or combination of features, from the tumor microenvironment drive drug resistance, and what the relative impact is of extracellular signals vs. intrinsic cell genetics in determining drug response. Sophisticated systems biology tools that can de-convolve a crowded network of signals and responses, as well as controllable microenvironments capable of providing discrete and tunable extracellular cues can help us begin to interrogate the high dimensional interactions governing drug resistance in patients.

A Single-Center Study Evaluating the Effects of a Novel Retinol and Cannabidiol Combination Topical on Facial Skin.

Background: While retinol is known to reduce the appearance of fine lines and wrinkles, it is associated with irritating effects. However, when combined with water soluble cannabidiol (CBD; CR Topical), CBD may act to reduce oxidative stress and inflammation, mitigating irritation from retinol and further improving the skin's appearance through independent anti-aging mechanisms. Objectives: To assess the efficacy and tolerability of CR-Topical for improving facial skin. Methods: In this prospective, single-center pilot study, 9 female patients and one male patient aged 20 to 53 years who presented with facial skin imperfections (visible pores, dehydration, roughness, and/or static/dynamic wrinkles) applied CR-Topical to the entire face once daily for 42 days. Outcomes were measured on days 1, 21, and 42 using the Global Ranking Scale (GRS) with Comprehensive Skin Analysis by the patient and senior investigator as well as by a blinded reviewer (board-certified plastic surgeon). Dynamic videos and static imagery were taken before and after treatment, and patient satisfaction surveys were completed. Results: Global improvement across all 13 domains was observed, with the greatest mean differences for visible pores (2.0; 95% CI, 1.5-2.5), dehydration (2.0; 95% CI, 1.4-2.6), surface roughness (1.8; 95% CI, 1.2-2.4), static wrinkles (1.8; 95% CI, 1.1-2.5), and dynamic wrinkles (1.6; 95% CI, 0.8-2.3). Patient satisfaction (100%) and willingness to recommend the product to others (90%) were high, and tolerability of CR-Topical was excellent. Conclusions: CR-Topical is effective at improving global skin quality, including static and dynamic wrinkles. This study also used 4-dimensional analysis in the evaluation, a novel and developing method.

Human Polyomavirus 9-An Emerging Cutaneous and Pulmonary Pathogen in Solid Organ Transplant Recipients.

IMPORTANCE: We describe the first report to our knowledge of cutaneous and systemic pathogenicity of human polyomavirus 9 in solid organ transplant recipients. OBJECTIVE: Three solid organ transplant recipients developed a widespread, progressive, violaceous, and hyperkeratotic skin eruption. All died from pulmonary and multiorgan failure around 1 year from onset of the rash. Routine clinical diagnostic testing could not identify any causative agent; therefore, samples and autopsies were investigated for novel pathogens using high-throughput sequencing. DESIGN, SETTING, AND PARTICIPANTS: This case series, including 3 solid organ transplant recipients who developed characteristic pink, violaceous, or brown hyperkeratotic papules and plaques throughout the body, was conducted at the Columbia University Medical Center. Lesional skin biopsies were collected from all 3 patients and subjected to high-throughput illumina sequencing for identification of microbial pathogens. Human polyomavirus 9 was identified in lesional skin biopsies. We subsequently collected ocular swabs, oral swabs, urine samples, and blood samples from patients, and organ tissues at autopsy in 1 patient. We investigated these samples for the presence of human polyomavirus 9 using in situ hybridization and quantitative polymerase chain reaction (PCR) assays. MAIN OUTCOMES AND MEASURES: A description of the clinical and pathologic findings of 3 patients. RESULTS: This case series study found that human polyomavirus 9 was detected in the skin biopsies of all 3 patients by a capture-based high-throughput sequencing method platform (VirCapSeq-VERT). Human polyomavirus 9 was also detected in blood, oral, ocular swabs, and urine by real-time polymerase chain reaction (PCR) assay. In situ hybridization and quantitative PCR assays were performed on the skin biopsies from 3 patients and lung autopsy of 1 patient, which showed the presence of human polyomavirus 9 messenger RNA transcripts, indicating active viral replication and pathogenesis in the skin and lungs. CONCLUSIONS AND RELEVANCE: Human polyomavirus 9 was associated with the widespread cutaneous eruption. All 3 patients had progression of cutaneous disease, accompanied by clinical deterioration, pulmonary failure, and death. One patient underwent autopsy and human polyomavirus 9 was identified in the lungs and paratracheal soft tissue. These findings suggest that human polyomavirus 9 may be associated with cutaneous and possibly pulmonary infection and death in solid organ transplant recipients.