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Background Immune checkpoint inhibitors (ICIs) have been incorporated into various clinical oncology guidelines for systemic treatment of advanced non-small cell lung cancers (aNSCLC). However, less than 50% (and 20%) of the patients responded to the therapy as a first (or second) line of therapy. PD-L1 immunohistochemistry (IHC) is an extensively studied biomarker of response to ICI, but results from this test have equivocal predictive power. In order to identify other biomarkers that support clinical decision-making around whether to treat with ICIs or not, we performed a retrospective study of patients with aNSCLC who underwent ICI-based therapy in the Mount Sinai Health System between 2014 and 2019. Methods We analyzed data from standard laboratory tests performed in patients as a part of the routine clinical workup during treatment, including complete blood counts (CBC) and a comprehensive metabolic panel (CMP), to correlate test results with clinical response and survival. Results Of 11,138 NSCLC patients identified, 249 had been treated with ICIs. We found associations between high neutrophil-to-lymphocyte ratio (NLR ≥ 5) and poor survival in ICI-treated NSCLC. We further observed that sustained high NLR after initiation of treatment had a more profound impact on survival than baseline NLR, regardless of PD-L1 status. Hazard ratios when comparing patients with NLR ≥ 5 vs. NLR < 5 are 1.7 ( p  = 0.02), 3.4 ( p  = 4.2 × 10 − 8 ), and 3.9 ( p  = 1.4 × 10 − 6 ) at baseline, 2–8 weeks, and 8–14 weeks after treatment start, respectively. Mild anemia, defined as hemoglobin (HGB) less than 12 g/dL was correlated with survival independently of NLR. Finally, we developed a composite NLR and HGB biomarker. Patients with pretreatment NLR ≥ 5 and HGB < 12 g/dL had a median overall survival (OS) of 8.0 months (95% CI 4.5–11.5) compared to the rest of the cohort with a median OS not reached (95% CI 15.9-NE, p  = 1.8 × 10 − 5 ), and a hazard ratio of 2.6 (95% CI 1.7–4.1, p  = 3.5 × 10 − 5 ). Conclusions We developed a novel composite biomarker for ICI-based therapy in NSCLC based on routine CBC tests, which may provide meaningful clinical utility to guide treatment decision. The results suggest that treatment of anemia to elevate HGB before initiation of ICI therapy may improve patient outcomes or the use of alternative non-chemotherapy containing regimens.

We use the GEOS‐Chem chemical transport model to interpret observations of tropospheric ozone from the Tropospheric Emission Spectrometer (TES) satellite instrument in summer 2005. Observations from TES reveal elevated ozone in the middle troposphere (500–400 hPa) across North Africa and the Middle East. Observed ozone abundances in the middle troposphere are at a maximum in summer and a minimum in winter, consistent with the previously predicted summertime “Middle East ozone maximum.” This summertime enhancement in ozone is associated with the Arabian and Sahara anticyclones, centered over the Zagros and Atlas Mountains, respectively. These anticyclones isolate the middle troposphere over northeast Africa and the Middle East, with westerlies to the north and easterlies to the south, facilitating the buildup of ozone. Over the Middle East, we find that in situ production and transport from Asia provides comparable contributions of 30–35% to the ozone buildup. Over North Africa, in situ production is dominant (at about 20%), with transport from Asia, North America, and equatorial Africa each contributing about 10–15% to the total ozone. We find that although the eastern Mediterranean is characterized by strong descent in the middle and upper troposphere in summer, transport from the boundary layer accounts for about 25% of the local Middle Eastern contribution to the ozone enhancement in the middle troposphere. This upward transport of boundary layer air is associated with orographic lifting along the Zagros Mountains in Iran and the Asir and Hijaz Mountain ranges in Saudi Arabia, and is consistent with TES observations of deuterated water.

We used the GEOS‐Chem model to investigate the impact of interannual variations in transport on summertime ozone abundances (between 1987 and 2006) in the middle troposphere over the Middle East. We found that ozone abundances fluctuated interannually by about ±7% (or ±6 ppbv from the 20‐year mean of ∼80 ppbv). In the 20‐year mean, ozone transported from Asia and ozone produced locally were the dominant sources of ozone, accounting for 31% and 23%, respectively, of ozone abundances over the Middle East, with an interannual variability of ±30% and ±15%, respectively. We found that the interannual variations in the Asian and local sources were related to the strengths of the South Asian High and the Arabian anticyclone, respectively. In years when the Asian influence was weaker in the region, transport from other areas, such as North America, was enhanced. Consequently, variations in ozone transported from Asia were strongly anti‐correlated with variations in ozone transported from North America, for example, with a correlation coefficient of r = −0.75. This trade‐off between transport from Asia and other regions was found to be linked to the position and strength of the subtropical westerly jet over central Asia. When the westerly jet is displaced poleward, transport of ozone from Asia is enhanced and transport from North America and other regions in the Northern Hemisphere is diminished. In contrast, when the jet is displaced equatorward, transport of ozone from Asia is diminished and transport from North America and other regions in the Northern Hemisphere is enhanced. These results suggest that climate‐related changes in the position of the westerly jet will have implications for the transport of pollution into the Middle East. Key Points The Tibetan High influences the variability in transport of Asian ozone The variability in local ozone is related to strength of the Iranian High The trade‐off in transport varies with the meridional shift of the westerly jet

Background The treatment algorithm for metastatic non-small cell lung cancers (NSCLCs) has been evolving rapidly due to the development of new therapeutic agents. Although guidelines are provided by National Comprehensive Cancer Network (NCCN) for treatment options according to biomarker testing results, sequentially applying the three main modalities (chemotherapy, targeted therapy and immunotherapy) remains an ad hoc practice in clinic. In light of recent FDA approval of dabrafenib and trametinib combination for metastatic NSCLCs with BRAF V600E mutation, one question arises due to insufficient clinical data is if the targeted therapy should be used before immunotherapy in patients with both BRAF V600E and PD-L1 expression. Case presentation We present a case of 74-year-old female, former smoker with metastatic lung adenocarcinoma. The BRAF V600E mutation among other abnormalities was identified by comprehensive genomic profiling. The patient had an excellent 2-year response to the combination of pemetrexed and sorafenib. The patient was then treated with dabrafenib due to the presence of the BRAF V600E mutation and intolerance to cytotoxic chemotherapy. Not only the patient had an 18-month durable response to dabrafenib, she experienced outstanding quality of life with no serious adverse effects. At the time of symptomatic progression, the patient was then treated with two cycles of pembrolizumab based on her positive PD-L1 staining (90%). She had early response and came off pembrolizumab due to side effects. Seven months after initiation of pembrolizumab, the patient is off all the therapy and is currently asymptomatic. The patient is surviving with metastatic disease for over 7 years as of to date. Conclusions By appropriately sequencing the three main modalities of systemic therapies, we are able to achieve long-term disease control with minimal side effects even in a geriatric patient with multiple comorbidities. We argue that it is reasonable to first use a BRAF inhibitor before considering immunotherapy for NSCLCs positive for both BRAF V600E and PD-L1.

Significant progress has been made in identifying the influence of different processes and emissions on the summertime enhancements of free tropospheric ozone (O3) at northern midlatitude regions. However, the exact contribution of regional emissions, chemical and transport processes to these summertime enhancements is still not well quantified. Here we focus on quantifying the influence of regional emissions on the summertime O3 enhancements over the Middle East, using updated reactive nitrogen (NOx) emissions. We then use the adjoint of the GEOS-Chem model with these updated NOx emissions to show that the global total contribution of lightning NOx on middle free tropospheric O3 over the Middle East is about 2 times larger than that from global anthropogenic sources. The summertime middle free tropospheric O3 enhancement is primarily due to Asian NOx emissions, with approximately equivalent contributions from Asian anthropogenic activities and lightning. In the Middle Eastern lower free troposphere, lightning NOx from Europe and North America and anthropogenic NOx from Middle Eastern local emissions are the primary sources of O3. This work highlights the critical role of lightning NOx on northern midlatitude free tropospheric O3 and the important effect of the Asian summer monsoon on the export of Asian pollutants.

Purpose Degenerative disc disease (DDD) is a common disabling condition for millions of individuals. Injection of xenogenic juvenile chondrocytes (XJC) into the disc space has been shown to have a therapeutic potential for disc repair. In the current study, XJC were injected extra-discally on neural structures in an in vivo rat hemilaminectomy model to compare the histological and behavioral effects on XJC and fibrin glue carrier. Methods Twenty-four rats were assigned to four groups: cells plus carrier, carrier alone, sham hemi-laminectomy, and a positive control (nerve root ligation). A right-sided hemilaminectomy was performed and the study material was placed on and around the exposed L4 nerve root and the spinal cord. Pre- and postoperatively mechanical allodynia was tested on the ipsilateral hind paw using the von Frey up-down method. The lumbar spines were harvested after 6 and 12 weeks for nerve histology and TNF-α quantification. Results After a brief period of hyperalgesia, the von Frey data indicate there are no adverse effects of placing XJC on spinal nerve roots in rats. However ligation of nerve root showed significant allodynia compared to the other groups. These behavioral data were supported by histological analyses. Conclusions While these results need to be confirmed over a larger period of time, they suggest that XJC transplantation into the disc space shows no adverse effect on nerve tissue.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo. A comprehensive analysis of antibody neutralization activity against a panel of authentic isolates and chimeric SARS-CoV-2 variants shows markedly diminished neutralizing activity against the variant B.1.351, first identified in South Africa.

Highlights the bridging character of drama-based foreign and second language teaching for intercultural learning. Drama here is not limited to theater-related work, but means the interplay between body and language in general, to include, for example, sports, dancing, singing, and storytelling. The major techniques and curricular structures of educational drama and its application in the foreign and second language classroom are introduced. What are the techniques, methods, strategies, and curricular structures that engage language learners in continuing dialogue between one's own culture and the one yet to be discovered? What comprises the language we speak in order to understand and be understood? Which body is it we communicate through and to? This volume answers these and other questions of the pedagogy of drama-based teaching across the foreign/second language curriculum and on all levels of the educational pyramid. There are two major issues currently discussed in drama-based foreign and second language methodology. The first is goal-oriented, asking whether the acquisition of accuracy or fluency is more important, and whether a controlled (learning through imitation) or an open (through improvisation) learning environment is more efficient. The second issue concerns using drama in language teaching: either its use is process-oriented, where drama becomes an immediate medium for language learning, or product-oriented, where it becomes primarily the reason for language learning. The book outlines the theoretical frameworks of both issues and introduces personal narrative, comparative observation, and analytical reflection, illuminating opportunities for learning at both ends of the seemingly contradictory poles of both issues.