In the absence of federal climate change policy, many states have adopted programs that encourage clean energy generation from sources such as wind, solar, and nuclear. Nuclear energy in particular ...remains an attractive option for a number of states pursuing clean energy policies because of its ability to generate electricity without producing any greenhouse gas emissions. Thus far, attempts by state regulators to encourage intrastate clean generation have also been trailed by fierce legal challenges from industry and consumer groups. This Comment distills the case law on state clean energy programs, and focuses on the legal issues that have been raised in litigation involving New York and Illinois's zero emission credit programs. It then proposes best practices that state regulators can adopt when designing clean energy programs so as to reduce litigation risk. By insulating their clean energy programs from legal challenges, states will be better equipped to achieve their individual climate change goals.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
2.
The Immunology of Melanoma Ko, Jennifer S
Clinics in laboratory medicine
37, Številka:
3
Journal Article
Recenzirano
The relatively high DNA mutational burden in melanoma allows for the creation of potentially "foreign," immune-stimulating neoantigens, and leads to its exceptional immunogenicity. Brisk ...tumor-infiltrating lymphocytes, a marker of immune editing, confer improved overall survival in melanoma, possibly due to reduced sentinel lymph node spread. Meanwhile, T-cell-stimulating drugs, so-called T-cell checkpoint inhibitors, which reverse peripheral tolerance-dependent tumor escape, have demonstrated unparalleled clinical success in metastatic melanoma. Markers to predict response to immunotherapy are currently imperfect, and the subject of intense research, which will guide the future of ancillary pathologic testing in this setting.
Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants ...remains limited.
Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes.
In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 26.9 and 513/696 73.7, respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2.
Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.
Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a ...chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17-mediated cascade via the IL-17R-Act1-TRAF4-MEKK3-ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17-induced sustained expansion of p63(+) basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17-induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17-dependent sustained activation of the TRAF4-ERK5 axis for keratinocyte proliferation and tumor formation.
Breast cancer is the most common cancer in reproductive age women. The aim of this study is to assess the knowledge, attitude and intention on fertility preservation among women diagnosed to have ...breast cancer. This is a multi-centre cross-sectional questionnaire study. Reproductive age women diagnosed with breast cancer attending Oncology, Breast Surgery and Gynaecology Clinics and support groups were invited to participate. Women filled in paper or electronic form of the questionnaire. 461 women were recruited and 421 women returned the questionnaire. Overall, 181/410 (44.1%) women had heard of fertility preservation. Younger age and higher education level were significantly associated with increased awareness of fertility preservation. Awareness and acceptance of the different fertility preservation methods in reproductive age women with breast cancer was suboptimal. However, 46.1% women felt that their fertility concerns affected their decision for cancer treatment in some way.
Objective
To compare the intercycle variation of serum anti‐Mullerian hormone (AMH) and antral follicle count (AFC) measurements over four consecutive menstrual cycles.
Design
Observational study ...with secondary analysis using data from two previous randomized controlled trials.
Patients
Seventy‐eight women from two previous randomized trials on the effect of dehydroepiandrosterone pretreatment on ovarian response in women undergoing in vitro fertilization (IVF) treatment.
Measurements
The intraclass correlation coefficients (ICC) for AFC and AMH across the four study cycles, as well as their predictive performance on poor ovarian response, were compared.
Results
No significant difference was observed in AMH (p = .608) across the four study cycles. AFC was significantly higher at 4 weeks before ovarian stimulation compared with 0, 8 and 12 weeks before ovarian stimulation (p < .05, Conover posthoc test). Both single‐measures and average‐measures ICC were significantly higher with AMH than with AFC. The areas under the receiver operating characteristic curve of the four AFC measurements in predicting poor ovarian response (defined as three or less oocytes retrieved) in the IVF cycle ranged from 0.657 to 0.743 with no significant difference (p > .05) among the four cycles, whereas those of the four AMH measurement ranged from 0.730 to 0.780 with no significant difference (p > .05) among the four cycles.
Conclusions
Although both AFC and AMH are good predictors of ovarian response, intercycle repeatability was significantly better with serum AMH than AFC measurement. Both have no significant difference in their predictive performance on poor ovarian response when assessed within three months before IVF treatment, hence allowing pre‐IVF assessment at more flexible timing.
Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor
cells (MDSC) represent one mechanism by which tumors induce ...T-cell suppression. Several factors pivotal to the accumulation
of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression
in RCC patients has been investigated.
Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before
and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were
examined. The in vitro effect of sunitinib on patient MDSC was evaluated.
Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR â and CD15 + CD14 â MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC
measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression,
an effect that could be reproduced by the depletion of MDSC in vitro . MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production
of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at â¥1.0 μg/mL. Sunitinib did not induce MDSC
maturation in vitro .
Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.
The antiangiogenic drug sunitinib is a receptor tyrosine kinase inhibitor with significant, yet not curative, therapeutic effects in metastatic renal cell carcinoma (RCC). Sunitinib is also an ...immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of nonresponder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to the spleens of tumor-bearing mice, independent of the capacity of sunitinib to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments showed that granulocyte macrophage colony-stimulating factor (GM-CSF) predicted sunitinib resistance and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for the regionalized effect of sunitinib upon host MDSC modulation and hypothesize that ancillary strategies to decrease such regionalized escape will enhance the potency of sunitinib as an immunomodulator and a cancer therapy.
Intravascular lobular capillary hemangioma (ILCH), or intravascular pyogenic granuloma, is relatively rare and likely underrecognized. We reviewed all ILCH cases from our institution confirmed ...pathologically from 2006 to 2019. Immunostains for smooth muscle actin and Wilms tumor 1 were performed on all cases and prior immunohistochemical stains were reviewed. Forty cases were identified (22 females; 18 males) with a median age of 53 years (range13 to 85 y). Clinically, all were well-circumscribed, stable to slow-growing raised/cystic skin lesions ranging from 1 to 40 mm. Most were located on the upper extremities (n=18), followed by head and neck (n=16). Vascular lesions were suspected clinically in one third. Of the consultation cases, provided differential diagnoses included Masson tumor, other hemangiomas, and vascular tumors of intermediate malignancy. The common histologic features were a well-circumscribed, lobular proliferation of closely packed capillaries with central ectatic vessels. The surrounding vascular wall was well-visualized in only half of the cases. About 30% of the cases were mitotically active (mean8 to 9 mitotic figures/10 HPFs), and 34% showed mild to moderate cytologic atypia. Hobnail features were present in 40% of cases. All cases were diffusely and strongly positive for Wilms tumor 1. Smooth muscle actin stains highlighted pericytes in all cases. Of the 20 cases with clinical follow-up (median40 mo), none recurred. ILCH commonly involves the upper extremities and a vascular tumor is suspected clinically in the minority. Mitotic activity and cytologic atypia, when present, can cause confusion with more aggressive vascular tumors. Recognition of this entity is essential as it is a benign lesion with no risk of recurrence following limited local excision.
Sunitinib is a receptor tyrosine kinase inhibitor (TKI) that is front-line therapy for metastatic renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block tumor cell and ...tumor vasculature cell signaling via several TKI receptors (i.e. vascular endothelial growth factor receptors VEGFRs, platelet-derived growth factors (PDGFs), and stem cell factors). Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine tumor models. This reduction in immune suppression provides a rationale for combining sunitinib with immunotherapy for the treatment of certain tumor types. Despite these encouraging findings, however, we have observed that sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in sunitinib-treated patients. While sunitinib reduced tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased GM-CSF expression. Additionally, in vitro and in vivo experiments showed that GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post nephrectomy in patients receiving sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing nephrectomy without prior sunitinib treatment. Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far, tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post sunitinib treatment, findings that parallel results from untreated tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells. GM-CSF's role in promoting MDSC survival in patient tumors is supported by the observation that GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic proteins, such as MMP9, MMP8, and IL-8 produced by tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic proteins. We propose that the development of sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.
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