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Searching for Earth-sized planets in data from Kepler's extended mission (K2) is a niche that still remains to be fully exploited. The TFAW survey is an ongoing project that aims to re-analyse all light curves in K2 C1–C8 and C12–C18 campaigns with a wavelet-based detrending and denoising method, and the period search algorithm TLS to search for new transit candidates not detected in previous works. We have analysed a first subset of 24 candidate planetary systems around relatively faint host stars (10.9 < K p < 15.4) to allow for follow-up speckle imaging observations. Using vespa and TRICERATOPS , we statistically validate six candidates orbiting four unique host stars by obtaining false-positive probabilities smaller than 1 per cent with both methods. We also present 13 vetted planet candidates that might benefit from other, more precise follow-up observations. All of these planets are sub-Neptune-sized with two validated planets and three candidates with sub-Earth sizes, and have orbital periods between 0.81 and 23.98 d. Some interesting systems include two ultra-short-period planets, three multiplanetary systems, three sub-Neptunes that appear to be within the small planet Radius Gap, and two validated and one candidate sub-Earths (EPIC 210706310.01, K2-411 b, and K2-413 b) orbiting metal-poor stars. [ABSTRACT FROM AUTHOR]

The clearance of apoptotic cells has an important role in the maintenance of tissue homeostasis and in the protection of tissues from the inflammatory and immunogenic contents of dying cells. A defect in the recognition and phagocytosis of apoptotic cells contributes to the development of chronic inflammation and autoimmune disorders. We have observed that compared with healthy donors, differentiated macrophages from patients with untreated systemic lupus erythematosus (SLE) showed decreased phagocytosis of apoptotic neutrophils. A TaqMan Low Density Array was designed to determine the mRNA expression levels of 95 apopto-phagocytic genes in differentiated non-phagocytosing and phagocytosing macrophages. In the macrophages of clinically and immunoserologically active SLE patients, 39 genes were expressed at lower levels than in the control macrophages. When inactive patients were compared with those with minor immunoserological abnormalities or patients in an immunoserologically active state, a relationship was observed between the altered gene expression profile and the disease state. In the macrophages of patients with engulfing apoptotic cells, an upregulation of genes involved in inflammation, autophagy, and signaling was observed. These results indicate that novel immune-pathological pathways are involved in SLE and suggest targets for potential therapeutic modulation. [ABSTRACT FROM AUTHOR]

Neuroendocrine (NE) cells comprise ~1% of epithelial cells in benign prostate and prostatic adenocarcinoma (PCa). However, they become enriched in hormonally treated and castration-resistant PCa (CRPC). In addition, close to 20% of hormonally treated tumors recur as small cell NE carcinoma (SCNC), composed entirely of NE cells, which may be the result of clonal expansion or lineage plasticity. Since NE cells do not express androgen receptors (ARs), they are resistant to hormonal therapy and contribute to therapy failure. Here, we describe the identification of glypican-3 (GPC3) as an oncofetal cell surface protein specific to NE cells in prostate cancer. Functional studies revealed that GPC3 is critical to the viability of NE tumor cells and tumors displaying NE differentiation and that it regulates calcium homeostasis and signaling. Since our results demonstrate that GPC3 is specifically expressed by NE cells, patients with confirmed SCNC may qualify for GPC3-targeted therapy which has been developed in the context of liver cancer and displays minimal toxicity due to its tumor-specific expression. © 2023 The Pathological Society of Great Britain and Ireland., (© 2023 The Pathological Society of Great Britain and Ireland.)

Ductal carcinoma in situ (DCIS) of the breast is often managed by lumpectomy and radiation or mastectomy, despite its indolent features. Effective non-invasive treatment strategies could reduce the morbidity of DCIS treatment. We have exploited the high heat shock protein 90 (HSP90) activity in premalignant and malignant breast disease to non-invasively detect and selectively ablate tumors using photodynamic therapy (PDT). PDT with the HSP90-targeting photosensitizer, HS201, can not only ablate invasive breast cancers (BCs) while sparing non-tumor tissue, but also induce antitumor immunity. We hypothesized that HS201-PDT would both non-invasively ablate DCIS and prevent progression to invasive BC. We tested in vitro selective uptake and photosensitivity of HS201 in DCIS cell lines compared to the non-selective parental verteporfin, and assessed in vivo antitumor efficacy in mammary fat pad and intraductal implantation models. Selective uptake of HS201 enabled treatment of intraductal lesions while minimizing toxicity to non-tumor tissue. The in vivo activity of HS201-PDT was also tested in female MMTV-neu mice prior to the development of spontaneous invasive BC. Mice aged 5 months were administered HS201, and their mammary glands were exposed to laser light. HS201-PDT delayed the emergence of invasive BC, significantly prolonged disease-free survival (DFS) ( p = 0.0328) and tended to improve overall survival compared to the no-treatment control ( p = 0.0872). Systemic administration of anti-PD-L1 was combined with HS201-PDT and was tested in a more aggressive spontaneous tumor model, HER2delta16 transgenic mice. A single PDT dose combined with anti-PD-L1 improved DFS compared to the no-treatment control, which was significantly improved with repetitive HS201-PDT given with anti-PD-L1 ( p = 0.0319). In conclusion, a non-invasive, skin- and tissue-sparing PDT strategy in combination with anti-PD-L1 antibodies effectively prevented malignant progression of DCIS to invasive BC. This non-invasive treatment strategy of DCIS may be safe and effective, while providing an option to reduce the morbidity of current conventional treatment for patients with DCIS. Clinical testing of HS201 is currently underway.

Background: The burden of surgical disease in refugee and internally displaced person (IDP) populations has not been well defined. Populations fleeing conflict are mobile, limiting the effectiveness of traditional sampling methods. We employed novel sampling and survey techniques to conduct a population-based surgical needs assessment amongst IDPs in Kerenik, West Darfur, Sudan, over 4 weeks in 2008., Methods: Satellite imagery was used to identify man-made structures. Ground teams were guided by GPS to randomly selected households. A newly created surgical needs survey was administered by surgeons to household members. One randomly selected individual answered demographic and medical history questions pertaining to themselves and first-degree blood relatives. All household members were offered a physical examination looking for surgical disease., Findings: There were 780 study participants; 82% were IDPs. A history since displacement of surgical and potentially surgical conditions was reported in 38% of respondents and by 73% of respondents in first-degree blood relatives. Surgical histories included trauma (gunshots, stabbings, assaults) (5% respondents; 27% relatives), burns (6% respondents; 14% relatives), and obstetrical problems (5% female respondents; 11% relatives). 1485 individuals agreed to physical examinations. Untreated surgical and potentially surgical disease was identified in 25% of participants., Interpretation: We identified and characterized a high burden of surgical and potentially surgical disease in an IDP population in West Darfur. Our study is unique in its direct assessment of a traumatized, mobile, vulnerable population. Health officials and agencies charged with the care of IDP and refugee populations should be aware of the high prevalence of surgical and potentially surgical conditions in these communities. This study adds to the growing body of evidence that investment in surgical resources may address a significant portion of the overall burden of disease in marginalized populations.

The oncogenic property of the Src homology phosphotyrosine phosphatase 2 (SHP2) is well-known, but developing specific inhibitors has been very difficult. Based on our previous reports that showed the importance of acidic residues surrounding SHP2 substrate phosphotyrosines for specific recognition, we have rationally designed and chemically synthesized a small-molecule SHP2 inhibitor named 4,4'-(4'-carboxy)-4-nonyloxy-[1,1'-biphenyl]-3,5-diyl)dibutanoic acid (CNBDA). Molecular modeling predicted that CNBDA packs well into the SHP2 active site and makes extended interactions primarily with positively charged and polar amino acids surrounding the active site. In vitro PTPase assays showed that CNBDA inhibits SHP2 with an IC 50 of 5 μM. However, the IC 50 of CNBDA toward SHP1, the close structural homologue of SHP2, was 125 μM, suggesting an approximately 25-fold effectiveness against SHP2 than SHP1. Because SHP2 is known for its positive role in breast cancer (BC) cell biology, we tested the effect of SHP2 inhibition with CNBDA in HER2-positive BC cells. Treatment with CNBDA suppressed cell proliferation in 2D culture, anchorage-independent growth in soft agar, and mammosphere (tumorisphere) formation in suspension cultures in a concentration-dependent manner. Furthermore, CNBDA inhibited EGF-induced signaling and expression of HER2 by inhibiting the PTPase activity of SHP2 in BC cells. These findings suggest that CNBDA is a promising anti-SHP2 lead compound with anti-BC cell effects., Competing Interests: The authors declare no competing financial interest.

The Src homology phosphatase 2 (SHP2) is a cytoplasmic enzyme that mediates signaling induced by multiple receptor tyrosine kinases, including signaling by the epidermal growth factor receptor (EGFR) family (EGFR1-4 or the human homologs HER1-4). In EGFR (HER1) and EGFR2 (HER2) signaling, SHP2 increases the half-life of activated Ras by blocking recruitment of Ras GTPase-activating protein (RasGAP) to the plasma membrane through dephosphorylation of docking sites on the receptors. However, it is unclear how SHP2 selectively recognizes RasGAP-binding sites on EGFR and HER2. In this report, we show that SHP2-targeted pTyr residues exist in a specific amino acid context that allows selective binding. More specifically, we show that acidic residues N-terminal to the substrate pTyr in EGFR and HER2 mediate specific binding by the SHP2 active site, leading to blockade of RasGAP binding and optimal signaling by the two receptors. Molecular modeling studies revealed that a peptide derived from the region of pTyr 992 -EGFR packs well and makes stronger interactions with the SHP2 active site than with the SHP1 active site, suggesting a built-in mechanism that enables selective substrate recognition by SHP2. A phosphorylated form of this peptide inhibits SHP2 activity in vitro and EGFR and HER2 signaling in cells, suggesting inhibition of SHP2 protein tyrosine phosphatase activity by this peptide. Although we do not expect this peptide to be a strong inhibitor by itself, we foresee that the insights into SHP2 selectivity described here will be useful in future development of active-site small molecule-based inhibitors., (© 2020 Hartman et al.)

Expression of human epidermal growth factor family member 3 (HER3), a critical heterodimerization partner with EGFR and HER2, promotes more aggressive biology in breast and other epithelial malignancies. As such, inhibiting HER3 could have broad applicability to the treatment of EGFR- and HER2-driven tumors. Although lack of a functional kinase domain limits the use of receptor tyrosine kinase inhibitors, HER3 contains antigenic targets for T cells and antibodies. Using novel human HER3 transgenic mouse models of breast cancer, we demonstrate that immunization with recombinant adenoviral vectors encoding full length human HER3 (Ad-HER3-FL) induces HER3-specific T cells and antibodies, alters the T cell infiltrate in tumors, and influences responses to immune checkpoint inhibitions. Both preventative and therapeutic Ad-HER3-FL immunization delayed tumor growth but were associated with both intratumoral PD-1 expressing CD8 + T cells and regulatory CD4 + T cell infiltrates. Immune checkpoint inhibition with either anti-PD-1 or anti-PD-L1 antibodies increased intratumoral CD8 + T cell infiltration and eliminated tumor following preventive vaccination with Ad-HER3-FL vaccine. The combination of dual PD-1/PD-L1 and CTLA4 blockade slowed the growth of tumor in response to Ad-HER3-FL in the therapeutic model. We conclude that HER3-targeting vaccines activate HER3-specific T cells and induce anti-HER3 specific antibodies, which alters the intratumoral T cell infiltrate and responses to immune checkpoint inhibition.

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

The number of primary total hip arthroplasties (THAs) performed in the United States each year continues to climb, as does the incidence of infectious complications. The changing profile of antibiotic-resistant bacteria has made preventing and treating primary THA infections increasingly complex. The goal of this review was to summarize (1) the published data concerning the risk of surgical site infection (SSI) after primary THA by type of bacteria and (2) the effect of potentially modifying factors. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, EMBASE, Web of Science, and PubMed were searched. Studies dated between 2001 and 2011 examining primary THA in adults were included. Meta-analysis of the collected data was performed. The pooled SSI rate was 2.5% (95% confidence interval [Cl], 1.4%-4.4%; P<.001; n=28,883). The pooled deep prosthetic joint infection (PJI) rate was 0.9% (95% Cl, 0.4%-2.2%; P<.001; n=28,883). The pooled rate of methicillin-resistant Staphylococcus aureus SSI was 0.5% (95% Cl, 0.2%-1.5%; P<.001; n=26,703). This is approximately 20% of all SSI cases. The pooled rate of intraoperative bacterial wound contamination was 16.9% (95% Cl, 6.6%-36.8%; P=.003; n=2180). All these results had significant heterogeneity. The postoperative risk of SSI was significantly associated with intraoperative bacterial surgical wound contamination (pooled rate ratio, 2.5; 95% Cl, 1.4%-4.6%; P=.001; n=19,049)., (Copyright 2014, SLACK Incorporated.)

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.

Nitrous acid (NA) is often presumed to cause base substitutions in organisms with double-stranded DNA as a direct consequence of oxidative deamination of adenine and of cytosine residues. Here we summarize evidence indicating that other mechanisms are involved in the case of NA-induced G/C-->A/T transition mutations. We present several models for pathways of NA mutagenesis that may account for our experimental results and overlapping data noted in the literature. One model proposes that the base substitution mutations observed are due to DNA alkylation damage mediated via nitrosation of polyamines and/or other ubiquitous cellular molecules. Other models assume that predisposing lesions, such as G-to-G cross-links, are first formed. The cross-links are pictured as leading to perturbations in DNA structure that allow subsequent opportunity for NA-induced deaminations of cytosine residues in their immediate vicinity. The deaminations preferentially result in G/C-->A/T transition mutations at sites highly dependent on adjoining base sequence context (i.e., in NA "mutational hotspots"). A final model proposes that NA-induced G/C-->A/T transition mutations arise mainly from oxidative deamination of guanosine residues and not from deamination of cytosine residues in duplex DNA.

Five points are emphasized: 1. Chemical interception and mere physical exclusion of mutagens and carcinogens constitute the major means by which mutations in cellular DNA are prevented. DNA repair processes comprise critical, but relatively minor, modes of genetic protection. 2. Disruption of a mutagen-interception defense mechanism can lead to substantial increases in mutagenesis and can preordain sites to eventual tumor formation. 3. Quantitation of the relative contributions of various blocking molecules is often simplified by the fact that protection can be calculated merely through knowledge of the measured concentration of the antimutagen and its rate of reaction with specific mutagens as measured in straightforward in vitro tests. 4. Two recently recognized defensive molecules, carnosine and ergothioneine, are put ++forward as examples of interesting chemical interceptor molecules. 5. Essentially all antimutagens are in fact "double-edged swords." Situations can be artificially constructed that can lead to generation of toxic species from molecules that are normally antimutagens; in isolated cases some of these interactions can be pictured as having deleterious consequences in vivo. This may be one reason why a number of important antimutagens are often sequestered, either in different tissues or by binding to dispensable macromolecules.

The most common fluorescent lamps in use today in homes and businesses in the United States, 'coolwhite' fluorescent lamps, emit light that is mutagenic for Salmonella. Strains that carry both a uvrB mutation and plasmid pKM101 are extremely susceptible to this light-induced mutation. Both base substitution and frameshift mutations can be induced without substantial lethal effects on the bacteria. Induced mutations accumulate essentially as a linear function of the time bacteria are exposed to illumination. Of Salmonella histidine-requiring strains with known nucleotide target sequences (Hartman et al., 1986; Cebula and Koch, 1989, 1990), strains either carrying one of the base substitution mutations, hisG428 and hisG46, or one of the frameshifts, hisC3076 and hisD6610, are most highly mutagenized whereas frameshift strains with hisD6580 and hisD3052 exhibit lower rates of mutagenesis. Mutagenicity does not appear to require the presence of oxygen. A filter blocking wavelengths below 370 nm eliminates mutagenesis. Polystyrene, cellulose acetate and, especially, mylar and glass filters reduce mutagenesis, indicating that at least some of the mutagenic effects can be attributed to leakage of radiations below 290 nm (far-ultraviolet light) from 'coolwhite' lamps. The more recently introduced fluorescent 'softwhite' lamps are roughly 10-fold less mutagenic at approximately equal light intensity. Incandescent light bulbs are much less mutagenic than are these fluorescent lamps. Our mutational data correlate closely with previous results in eukaryotic cells (Jacobson and Krell, 1982). A uvrB recA Salmonella double mutant is hypersensitive to the lethal effects of coolwhite fluorescent light, even when illuminated through the lids of glass Petri dishes. Thus, appropriate Salmonella strains would appear to be simple and useful screens for both the mutagenic and the lethal activities of fluorescent lamps. These systems are amenable to classroom laboratory use as relatively safe and effective means of demonstrating environmental mutagenesis.

Singlet molecular oxygen was generated by illumination of phenosafranin in phosphate buffer at pH 7.5. Relative efficiencies of various imidazole compounds to form endoperoxides were assayed by following at 25 degrees C the rate of light- and imidazole-dependent bleaching of N,N-dimethyl-4-nitrosoaniline. Of over 30 imidazole compounds tested, imidazole-4-acetic acid, a major catabolite of histamine in mammals, exhibited the highest activity. L-Carnosine (beta-alanyl-L-histidine), a natural dipeptide prevalent in striated muscle of mammals, possessed several properties important for a physiologically significant scavenger of singlet oxygen. On a molar basis, this readily water-soluble C-terminal histidine dipeptide reacted with singlet oxygen two- to four-fold faster than free L-histidine and approximately two-fold faster than the N-terminal L-histidine dipeptides tested. Furthermore scavenging ability of L-carnosine did not appreciably increase or decrease with time of reaction, in contrast to behaviors exhibited by a number of other imidazole compounds that included some other C-terminal L-histidine dipeptides. The fungal metabolite, ergothioneine, blocked singlet oxygen generation by illuminated phenosafranin.

Ergothioneine, a novel imidazole sulfhydryl/thione compound formed in millimolar amounts by fungi, is a potentially important defense against electrophiles and free radicals. Protection may well occur both in organisms that synthesize ergothioneine and in animals including man that ingest and store ergothioneine in red blood cells, the liver, seminal fluid, and central nervous system. Ergothioneine blocks the mutagenicity for Salmonella strain TA1950 (hisG46 uvrB) of the nitrosation products of spermidine to an extent that is approximately proportional to the ergothioneine concentration. Ergothioneine also alleviates mutagenicity of cumene and t-butyl hydroperoxides but does not react with N-methyl-N'nitro-N-nitrosoguanidine as does the cysteinyl sulfhydryl compound, glutathione.

A mutation at the divD locus in Salmonella typhimurium confers a round-cell morphology and enhances cell division under certain growth conditions.

Incubation of Salmonella typhimurium under anoxic conditions (0.1% oxygen or less) results in a substantial decrease in small (3-and 6-basepair) deletions in an A/T-rich region of the hisG gene in the hisG428 ochre mutant and also decreases the frequency of minus frameshift mutations in G/C-rich sequences in the his-D3052 and hisC3076 mutants. In contrast, the frequency of G/C-----A/T transition mutations increases substantially during anoxic growth of hisG46. Growth of revertants of strains carrying accessory deletions in the uvrB region of the Salmonella chromosome is drastically impaired on glucose minimal medium when oxygen partial pressures are below 0.1% oxygen.

An aryl-monoalkyl triazene, methyl-p-tolyl triazene (MTT) and a cyclic triazene (delta2-triazoline) are direct-acting mutagens for Salmonella typhimurium bacteria and for cell-free Hemophilus influenzae DNA. MTT causes reversion of the hisG46 base-substitution mutation, but no reversion of the hisD3052 frameshift mutation. Induced mutation frequency is not strongly influenced by modifications in the genetic background of the S. typhimurium Ames tester strains, but is mildly enhanced by the addition of a pool of amino acids to the plating medium and is strongly enhanced by liquid preincubation before plating.

Bacteriophages P22, T4+, and T4os (osmotic shock-resistant mutant with altered capsids) were diluted in 0.85% NaCl and exposed to gamma irradiation (2.79 Gy/min) at room temperature (24 degrees C). T4+ was more sensitive to inactivation than was P22, and the T4os mutant was even more sensitive than T4+. Catalase exhibited a strong protective effect and superoxide dismutase a weaker protection, indicating that H2O2 or some product derived therefrom was predominant in causing inactivation of plaque formation. Low but significant (0.1-0.3 mM) reduced glutathione (GSH) enhanced phage inactivation, but a higher (1 mM) GSH concentration protected. A similar effect was found for the polyamine, spermidine. In contrast, 0.1 mM L-ergothioneine (2-thiol-L-histidine betaine) exhibited strong protection and 1 mM afforded essentially complete protection. L-Ergothioneine is present in millimolar concentrations in some fungi and is conserved up to millimolar concentrations in critical tissues when consumed by man. L-Histidine and two histidine-containing dipeptides, carnosine and anserine, protected at a concentration of 1 mM, a level at which they are present in striated muscles of various animals.

Rapid spot-test screening of antischistosomal agents reveals that hycanthone is a potent frameshift mutagen while the closely related compound, miracil D, is nonmutagenic in Salmonella. Both hycanthone and miracil D are frameshift mutagens for T4 bacteriophage during growth in Escherichia coli.