Tissue biopsy is the standard diagnostic procedure for cancer. Biopsy may also provide material for genotyping, which can assist in the diagnosis and selection of targeted therapies but may fall ...short in cases of inadequate sampling, particularly from highly heterogeneous tumors. Traditional tissue biopsy suffers greater limitations in its prognostic capability over the course of disease, most obviously as an invasive procedure with potential complications, but also with respect to probable tumor clonal evolution and metastasis over time from initial biopsy evaluation. Recent work highlights circulating tumor DNA (ctDNA) present in the blood as a supplemental, or perhaps an alternative, source of DNA to identify the clinically relevant cancer mutational landscape. Indeed, this noninvasive approach may facilitate repeated monitoring of disease progression and treatment response, serving as a means to guide targeted therapies based on detected actionable mutations in patients with advanced or metastatic solid tumors. Notably, ctDNA is heralding a revolution in the range of genomic profiling and molecular mechanisms to be utilized in the battle against cancer. This review will discuss the biology of ctDNA, current methods of detection and potential applications of this information in tumor diagnosis, treatment, and disease prognosis. Conventional classification of tumors to describe cancer stage follow the TNM notation system, heavily weighting local tumor extent (T), lymph node invasion (N), and detectable metastasis (M). With recent advancements in genomics and bioinformatics, it is conceivable that routine analysis of ctDNA from liquid biopsy (B) may make cancer diagnosis, treatment, and prognosis more accurate for individual patients. We put forward the futuristic concept of TNMB tumor classification, opening a new horizon for precision medicine with the hope of creating better outcomes for cancer patients.
Recent studies describe a heterogeneous population of cells of the myeloid lineage, termed myeloid derived suppressor cells (MDSC), which are observed with increased prevalence in the peripheral ...blood and tumor microenvironment of cancer patients, including pancreatic cancer. Accumulation of MDSC in the peripheral circulation has been related to extent of disease, and correlates with stage. MDSC have primarily been implicated in promoting tumor growth by suppressing antitumor immunity. There is also compelling evidence MDSC are also involved in angiogenesis and metastatic spread. Two main subsets of MDSC have been identified in cancer patients: a monocytic subset, characterized by expression of CD14, and a granulocytic subset characterized by expression of CD15. Both subsets of MDSC actively suppress host immunity through a variety of mechanisms including production of reactive oxygen species and arginase. Just as in humans, accumulation of monocytic and granulocytic MDSC has been noted in the bone marrow, spleen, peripheral circulation, and tumors of tumor bearing mice. Successful targeting of MDSC in mice is associated with improved immune responses, delayed tumor growth, improved survival, and increased efficacy of vaccine therapy. By further elucidating mechanisms of MDSC recruitment and maintenance in the tumor environment, strategies could be developed to reverse immune tolerance to tumor. We discuss here what is currently known about MDSC as well as some potential strategies targeting MDSC in the context of our work on pancreatic cancer and recent literature. Due to the number of new reports on MDSC, the most pertinent ones have been selected.
To reveal how cells exit human pluripotency, we designed a CRISPR-Cas9 screen exploiting the metabolic and epigenetic differences between naïve and primed pluripotent cells. We identify the tumor ...suppressor, Folliculin(FLCN) as a critical gene required for the exit from human pluripotency. Here we show that FLCN Knock-out (KO) hESCs maintain the naïve pluripotent state but cannot exit the state since the critical transcription factor TFE3 remains active in the nucleus. TFE3 targets up-regulated in FLCN KO exit assay are members of Wnt pathway and ESRRB. Treatment of FLCN KO hESC with a Wnt inhibitor, but not ESRRB/FLCN double mutant, rescues the cells, allowing the exit from the naïve state. Using co-immunoprecipitation and mass spectrometry analysis we identify unique FLCN binding partners. The interactions of FLCN with components of the mTOR pathway (mTORC1 and mTORC2) reveal a mechanism of FLCN function during exit from naïve pluripotency.
Electrochemical disinfection (ECD) has become an important blackwater disinfection technology. ECD is a promising solution for the 2 billion people without access to conventional sanitation practices ...and in areas deficient in basic utilities (e.g., sewers, electricity, waste treatment). Here, we report on the disinfection of blackwater using potential cycling compared to potentiostatic treatment methods in chloride-containing and chloride-free solutions of blackwater (i.e., untreated wastewater containing feces, urine, and flushwater from a toilet). Potentiodynamic treatment is demonstrated to improve disinfection energy efficiency of blackwater by 24% and 124% compared to static oxidation and reduction methods, respectively. The result is shown to be caused by electrochemical advanced oxidation processes (EAOP) and regeneration of sp2-surface-bonded carbon functional groups that serve the dual purpose of catalysts and adsorption sites of oxidant intermediates. Following 24 h electrolysis in blackwater, electrode fouling is shown to be minimized by the potential cycling method when compared to equivalent potentiostatic methods. The potential cycling current density is 40% higher than both the static oxidative and reductive methods. This work enhances the understanding of oxygen reduction catalysts using functionalized carbon materials and electrochemical disinfection anodes, both of which have the potential to bring a cost-effective, energy efficient, and practical solution to the problem of disinfecting blackwater.
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•Demonstration of improved blackwater disinfection using potentiodynamic methods.•Improvement is linked to control of electrode surface chemistry.•A surface chemical mechanism is proposed for different electrolytes.•Method shown to be far more efficient than static potential methods.
Protein kinase B (PKB) is a proto-oncogene that is activated in signaling pathways initiated by phosphoinositide 3-kinase. Chromatographic separation of brain cytosol revealed a kinase activity that ...phosphorylated and activated PKB only in the presence of phosphatidylinositol-3,4,5-trisphosphate PtdIns(3,4,5)P$_3$. Phosphorylation occurred exclusively on threonine-308, a residue implicated in activation of PKB in vivo. PtdIns(3,4,5)P$_3$ was determined to have a dual role: Its binding to the pleckstrin homology domain of PKB was required to allow phosphorylation by the upstream kinase and it directly activated the upstream kinase.
Oceanography and Marine Biology: An Annual Review remains one of the most cited sources in marine science and oceanography. The ever-increasing interest in work in oceanography and marine biology and ...its relevance to global environmental issues, especially global climate change and its impacts, creates a demand for authoritative refereed reviews summarizing and synthesizing the results of recent research. For more than 50 years, OMBAR has been an essential reference for research workers and students in all fields of marine science.This volume considers such diverse topics as optimal design for ecosystem-level ocean observatories, the oceanography and ecology of Ningaloo, human pressures and the emergence of novel marine ecosystems and priority species to support the functional integrity of coral reefs. Six of the nine peer-reviewed contributions in Volume 58 are available to read Open Access via the links on the Routledge.com webpage.An international Editorial Board ensures global relevance and expert peer review, with editors from Australia, Canada, Hong Kong, Ireland, Singapore, South Africa and the United Kingdom. The series volumes find a place in the libraries of not only marine laboratories and oceanographic institutes, but also universities worldwide.
Background The dermatological aspects of male genital lichen sclerosus (MGLSc) have not received much prominence in the literature. Sexual morbidity appears under‐appreciated, the role of histology ...is unclear, the relative places of topical medical treatment and circumcision are not established, the prognosis for sexual function, urinary function and penis cancer is uncertain and the pathogenesis has not been specifically studied although autoimmunity (as in women) and HPV infection have been mooted.
Objective To illuminate the above by analysing the clinical parameters of a large series of patients with MGLSc.
Methods A total of 329 patients with a clinical diagnosis of MGLSc were identified retrospectively from a dermatology‐centred multidisciplinary setting. Their clinical and histopathological features and outcomes have been ed from the records and analysed by simple descriptive statistics.
Results The collation and analysis of clinical data derived from the largest series of men with MGLSc ever studied from a dermatological perspective has been achieved. These data allow the conclusions below to be drawn.
Conclusions MGLSc is unequivocally a disease of the uncircumcised male; the adult peak is late in the fourth decade; dyspareunia is a common presenting complaint; non‐specific histology requires careful interpretation; most men are either cured by topical treatment with ultrapotent steroid (50–60%) or by circumcision (>75%); effective and definitive management appears to abrogate the risk of developing penile squamous cell carcinoma; urinary contact is implicated in the pathogenesis of MGLSc; HPV infection and autoimmunity seem unimportant.
IMPORTANCE: Specialist palliative care benefits patients undergoing medical treatment of cancer; however, data are lacking on whether patients undergoing surgery for cancer similarly benefit from ...specialist palliative care. OBJECTIVE: To determine the effect of a specialist palliative care intervention on patients undergoing surgery for cure or durable control of cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a single-center randomized clinical trial conducted from March 1, 2018, to October 28, 2021. Patients scheduled for specified intra-abdominal cancer operations were recruited from an academic urban referral center in the Southeastern US. INTERVENTION: Preoperative consultation with palliative care specialists and postoperative inpatient and outpatient palliative care follow-up for 90 days. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was physical and functional quality of life (QoL) at postoperative day (POD) 90, measured by the Functional Assessment of Cancer Therapy–General (FACT-G) Trial Outcome Index (TOI), which is scored on a range of 0 to 56 with higher scores representing higher physical and functional QoL. Prespecified secondary end points included overall QoL at POD 90 measured by FACT-G, days alive at home until POD 90, and 1-year overall survival. Multivariable proportional odds logistic regression and Cox proportional hazards regression models were used to test the hypothesis that the intervention improved each of these end points relative to usual care in an intention-to-treat analysis. RESULTS: A total of 235 eligible patients (median IQR age, 65.0 56.8-71.1 years; 141 male 60.0%) were randomly assigned to the intervention or usual care group in a 1:1 ratio. Specialist palliative care was received by 114 patients (97%) in the intervention group and 1 patient (1%) in the usual care group. Adjusted median scores on the FACT-G TOI measure of physical and functional QoL did not differ between groups (intervention score, 46.77; 95% CI, 44.18-49.04; usual care score, 46.23; 95% CI, 43.08-48.14; P = .46). Intervention vs usual care group odds ratio (OR) was 1.17 (95% CI, 0.77-1.80). Palliative care did not improve overall QoL measured by the FACT-G score (intervention vs usual care OR, 1.09; 95% CI, 0.75-1.58), days alive at home (OR, 0.87; 95% CI, 0.69-1.11), or 1-year overall survival (hazard ratio, 0.97; 95% CI, 0.50-1.88). CONCLUSIONS AND RELEVANCE: This randomized clinical trial showed no evidence that early specialist palliative care improves the QoL of patients undergoing nonpalliative cancer operations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03436290
Protein kinase B (PKB) is activated in response to phosphoinositide 3-kinases and their lipid products phosphatidylinositol 3,4,5-trisphosphate PtdIns(3,4,5)P$_3$ and PtdIns(3,4)P$_2$ in the ...signaling pathways used by a wide variety of growth factors, antigens, and inflammatory stimuli. PKB is a direct target of these lipids, but this regulation is complex. The lipids can bind to the pleckstrin homologous domain of PKB, causing its translocation to the membrane, and also enable upstream, Thr$^{308}$-directed kinases to phosphorylate and activate PKB. Four isoforms of these PKB kinases were purified from sheep brain. They bound PtdIns(3,4,5)P$_3$ and associated with lipid vesicles containing it. These kinases contain an NH$_2$-terminal catalytic domain and a COOH-terminal pleckstrin homologous domain, and their heterologous expression augments receptor activation of PKB, which suggests they are the primary signal transducers that enable PtdIns(3,4,5)P$_3$ or PtdIns(3,4)P$_2$ to activate PKB and hence to control signaling pathways regulating cell survival, glucose uptake, and glycogen metabolism.
The New Plantation examines the controversial relationship between predominantly White NCAA Division I Institutions (PWI s) and black athletes, utilizing an internal colonial model. It provides a ...much-needed in-depth analysis to fully comprehend the magnitude of the forces at work that impact black athletes experiences at PWI s. Hawkins provides a conceptual framework for understanding the structural arrangements of PWI s and how they present challenges to Black athletes academic success; yet, challenges some have overcome and gone on to successful careers, while many have succumbed to these prevailing structural arrangements and have not benefited accordingly. The work is a call for academic reform, collective accountability from the communities that bear the burden of nurturing this athletic talent and the institutions that benefit from it, and collective consciousness to the Black male athletes that make of the largest percentage of athletes who generate the most revenue for the NCAA and its member institutions. Its hope is to promote a balanced exchange in the athletic services rendered and the educational services received.
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