The Role of Local Therapy for Oligo-Progressive Disease in Oncogene-Addicted Non-Small-Cell Lung Cancer.

Purpose: We first described the role of local radiation therapy (LT) for oligoprogressive disease (OPD) on targeted therapy in 2012. Here, we present an updated and larger data set and extend the analysis beyond EGFR and ALK. Methods: A retrospective review of patients with metastatic NSCLC harboring EGFR/BRAF V600E mutations, or ALK/ROS1/RET rearrangements, who had OPD on respective tyrosine-kinase inhibitor (TKI) and treated with LT was performed. OPD was defined as disease progression on therapy in ≤5 sites. PFS1 (progression-free survival 1) was defined as time from initiation of TKI-containing regimen to the first course of LT for OPD. Subsequent PFS times (eg, PFS2, PFS3) were defined as time from prior LT to subsequent LT, switch of systemic therapy, death, or loss to follow-up, whichever occurred first. Extended-PFS was defined as time from the first day of the first LT course to the day of change in systemic therapy, death, or loss to follow-up, whichever came first. Results: Eighty-nine patients were identified. In 75.4% of the LT courses, a single lesion was treated. Median PFS1 was 10.2 months (95% CI, 8.7-13.1) and median Extended-PFS was 6.7 months (95% CI, 4.9-8.3). Extended-PFS was similar across different oncogenic drivers; 51.4% of patients who underwent LT to a single site had only 1 site on next disease progression. Conclusions: LT is effective in prolonging treatment duration on TKI in oncogene-addicted NSCLC across multiple oncogenes.

Pilot Curriculum for Continued Professional Development of Radiation Oncology Nurses.

Purpose: Limited structured educational programs are available for the continued professional development of radiation oncology nurses. In this study, we evaluated a pilot curriculum focusing on clinical workflow and toxicity management for radiation oncology nurses at a single university-affiliated medical center network. Methods and Materials: Based on a previous multi-institutional needs assessment, a targeted curriculum on clinical workflow and toxicity management was developed, including didactic lectures, written disease-specific toxicity management guidelines, and standardized medication/laboratory order preference lists in the electronic health record. An anonymized survey was circulated to all participants pre- and postcurriculum. The survey was composed of Likert-type subjective questions and 11 objective knowledge-based questions (KBQs). Paired Likert-type data were analyzed using Wilcoxon signed ranks test. Objective question data were compared with the McNamar's mid P test. Results: Thirteen nurses participated in the pilot curriculum and 100% completed pre- and post curriculum surveys. After the didactics, nurses reported a significant increase in their understanding of the responsibilities of a nurse and overall process of care and their ability to explain computed tomography simulation, as well as their ability to assess, manage, and grade radiation-related toxicities (P < .01). There was significant improvement in the percent of correct answers on objective KBQs from a baseline of 52% to 80% after the curriculum (P < .01). Qualitatively, 70% (9/13) of nurses rated the curriculum as "extremely useful" and 30% (4/13) as "quite useful." Conclusions: Our pilot curriculum using a combination of in-person formal didactics, toxicity management guidelines, and electronic health record based order preference lists was well-received and showed promising results on KBQ assessment. This work may be used to guide the development of larger curricula for nurse onboarding and continuing education in a multicenter setting.

Epidemiologic and Clinical Features of Mpox-Associated Deaths - United States, May 10, 2022-March 7, 2023.

As of March 7, 2023, a total of 30,235 confirmed and probable monkeypox (mpox) cases were reported in the United States,† predominantly among cisgender men§ who reported recent sexual contact with another man (1). Although most mpox cases during the current outbreak have been self-limited, cases of severe illness and death have been reported (2-4). During May 10, 2022-March 7, 2023, 38 deaths among persons with probable or confirmed mpox¶ (1.3 per 1,000 mpox cases) were reported to CDC and classified as mpox-associated (i.e., mpox was listed as a contributing or causal factor). Among the 38 mpox-associated deaths, 94.7% occurred in cisgender men (median age = 34 years); 86.8% occurred in non-Hispanic Black or African American (Black) persons. The median interval from symptom onset to death was 68 days (IQR = 50-86 days). Among 33 decedents with available information, 93.9% were immunocompromised because of HIV. Public health actions to prevent mpox deaths include integrated testing, diagnosis, and early treatment for mpox and HIV, and ensuring equitable access to both mpox and HIV prevention and treatment, such as antiretroviral therapy (ART) (5).

The Kelowna template for combined intracavitary and interstitial brachytherapy for gynecologic malignancies: Design, application, treatment planning, dosimetric and treatment outcomes.

PURPOSE: We report the feasibility, experience, and early outcomes of the combined intracavitary and interstitial dedicated applicator using the Kelowna GYN template (Varian, Palo Alto, CA). METHODS AND MATERIALS: The Kelowna GYN template is CT compatible and used for the treatment of gynecologic cancers. In cases with patients that have an intact uterus, a modified applicator system using the Kelowna GYN template and a 3D printed adapter piece allows for compatibility with an intrautaerine tandem. RESULTS: We reviewed the treatment course of 23 patients comprising of 86 fractions of HDR treatment. Median D90 for cervical tumors (n = 7) was 82.4 Gy (range 77.7-92.6); for postoperative cervical tumors (n = 2) was 73.9 Gy (range 72.0-5.8); for vaginal tumors (n = 4) was 85.8 Gy (range 79.8-88.1); for recurrent endometrial (n = 10) was 86.9 Gy (range 74.8-103.2). Median EQD2 D2cc for bladder was 72.4 Gy (range 47.7-99.4), for rectum was 61.2 Gy (range 52.4-80.6), and for sigmoid colon of 50.5 Gy (44.3-66.9). At a median follow-up of 12 months, 2 patients had a local recurrence. Two patients had distant recurrence: one with carcinomatosis at 6 months, and one with pulmonary metastases at 3 months. No patients had late grade three toxicities. CONCLUSIONS: Our single institutional experience supports the use of the Kelowna template as a robust system as a combined IC-IS applicator resulting in versatile and reproducible implants for a variety of gynecologic malignancies.

The role of concomitant chemoradiotherapy versus radiation alone in T1-3N0 HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma.

OBJECTIVE: To evaluate the role of curative intent concurrent chemoradiation (CCRT) vs radiation (RT) alone for T1-T3N0 HPV-positive and HPV-negative oropharyngeal squamous cell cancer (OPSCC). METHODS: The NCDB was queried for patients diagnosed between 2010 and 2017 with cT1-3N0M0 OPSCC treated with definitive RT or CCRT. Univariable analysis (UVA) and multivariable analysis (MVA) Cox regression analysis was performed with OS as the endpoint. Propensity score matching (PSM) 1:1 was performed. Interaction test to assess heterogeneity of treatment effect. RESULTS: A total of 2830 patients were queried. On MVA, CCRT was associated with improved OS for T3N0 tumors (HR 0.49; 95% CI 0.39-0.63) but not for T1N0 (HR 1.43; 95% CI 0.99-2.07) and T2N0 (HR 0.92; 95% CI 0.75-1.13). For T3 patients, CCRT improved OS for HPV-negative (HR 0.43; 95% CI 0.31-0.59) and HPV-positive tumors (HR 0.39; 95% CI 0.25-0.61). After PSM, CCRT was not statistically different to RT for patients with T1-2N0 HPV-negative tumors (HR 1.10; 95% CI 0.85-1.43; p = 0.48) and T1-2N0 HPV-positive tumors (HR 1.15; 95% CI 0.79-1.68; p = 0.45). After PSM, CCRT improved OS compared to RT alone for patients with T3N0 HPV-negative (HR 0.43; 95% CI 0.31-0.59; p < 0.01) and HPV-positive tumors (HR 0.39; 95 %CI 0.25-0.61; p < 0.01). CONCLUSIONS: CCRT is associated with improved OS in HPV-positive and HPV-negative T3N0 OPSCC. RT alone vs. CCRT demonstrated similar OS for T1-T2N0 OPSCC for both HPV negative and HPV positive tumors.

Gynecologic interstitial brachytherapy curriculum using a low-cost phantom with ultrasound workshop and a treatment planning workshop is effective.

PURPOSE/OBJECTIVE(S): Standardized simulation training geared towards interstitial brachytherapy (IS BT) for gynecologic malignancies is lacking in radiation oncology resident education. We developed and implemented a curriculum for IS BT training with (1) lecture on equipment, workflow, and guidelines, (2) hands-on ultrasound-guided IS BT workshop, and (3) treatment planning workshop. METHODS AND MATERIAL: The cost in materials of each phantom was approximately $66. After a lecture, two alternating workshops were performed. The first session consisted of a hands-on ultrasound-guided IS BT workshop with one resident imaging the phantom with a transabdominal ultrasound probe and the other resident implanting the phantom with needles. A second session consisted of a hands-on treatment planning workshop using BrachyVision and an l-Q spreadsheet with the following objectives: coverage goal, meeting D2cc constraints, and minimizing V200. The primary outcome was improvement in knowledge assessed with Likert-style questions and objective knowledge-based questions (KBQs). RESULTS: Four of the seven medical residents that participated in this curriculum had prior IS BT experience. Residents reported significantly improved knowledge regarding gynecologic IS BT equipment and procedure, evaluating gynecologic anatomy using ultrasound, CT simulation, contouring, and plan review (overall median pre-session subjective score 2 (1) -(3) versus post-session score 4 (3) -(4, p < 0.01). Residents demonstrated improvement in answering KBQs correctly from 44% correct at baseline to 88% after completion of the curriculum (p < 0.01). All residents "Agree" and "Strongly Agree" the session was an effective learning experience. CONCLUSIONS: Residents participating in phantom training with an ultrasound curriculum and a treatment planning session is effective for improving knowledge and skills in IS BT for radiation oncology residents.

Improving the Pediatric Patient Experience During Radiation Therapy-A Children's Oncology Group Study.

PURPOSE: Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods. METHODS AND MATERIALS: A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children. RESULTS: Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality. CONCLUSIONS: Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers.

Impact of neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) on R0 resection rate for borderline resectable and locally advanced pancreatic cancer.

BACKGROUND: The role of neoadjuvant stereotactic body radiation therapy (SBRT) in patients with borderline resectable pancreas cancer (BRPC) and locally advanced pancreas cancer (LAPC) remains controversial. METHODS: We retrospectively evaluated BRPC and LAPC patients treated at our institution who underwent 2-3 months of chemotherapy followed by SBRT to a dose of 30-33 Gy. Overall survival (OS) and recurrence-free survival (RFS) were estimated and compared by Kaplan-Meier and log-rank methods. RESULTS: We identified 103 (85 BRPC and 18 LAPC) patients treated per our neoadjuvant paradigm between 2011 and 2018, with resectability based on NCCN definitions. Median follow up was 25 months. Of patients completing neoadjuvant therapy, 73 (71%) underwent definitive resection. Seventy-one (97%) patients with definitively resected tumors had R0 resection and 5 (7%) had a complete pathologic response CR to neoadjuvant therapy. The median overall survival (OS) of the cohort was 24 months. Those with a complete or marked pathologic response had significantly better OS than those with a moderate response (41 vs 24 months, p < 0.02) and patients unable to undergo definitive surgery (17 months, p < 0.0003). Six resected patients experienced grade ≥3 surgical complications. CONCLUSIONS: Neoadjuvant chemotherapy and SBRT are associated with promising pathologic response rates and R0 resection rates, with acceptable perioperative morbidity.

TMEM16A/ANO1 suppression improves response to antibody-mediated targeted therapy of EGFR and HER2/ERBB2.

TMEM16A, a Ca2+ -activated Cl- channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl- channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl- channel inhibition. Treatment of HNSCC cells with cetuximab, a monoclonal antibody targeting EGFR, and simultaneous TMEM16A suppression led to a pronounced loss of viability. Biochemical analyses of cells subjected to TMEM16A inhibitors or expressing chloride-deficient forms of TMEM16A provide further evidence that TMEM16A channel function may play a role in regulating EGFR/HER2 signaling. These data demonstrate that TMEM16A regulates EGFR and HER2 in growth and survival pathways. Furthermore, in the absence of TMEM16A cotargeting, tumor cells may acquire resistance to EGFR/HER inhibitors. Finally, targeting TMEM16A improves response to biological therapies targeting EGFR/HER family members.

Current views and challenges on clinical cholera.

Cholera, an acute diarrheal infection has become a major global threat. Vibrio cholerae the causative agent of cholera has been responsible for six previous pandemics since 1817 that spanned four continents and Australia with the seventh pandemic ongoing since 1961. Two serogroups of V. cholerae O1 and O139 have the ability to secrete the enterotoxin with potential to cause epidemics. The prior six pandemics were caused by the classical biotype of the O1 serogroup. However, the emergence of the El Tor biotype and subsequent variants of El Tor with classical traits are the main isolates in the seventh pandemic. Cholera outbreaks have increased among vulnerable communities affected by war, earthquakes, conflicts and famines. Annually, 2.9 million cases of cholera occur globally in 69 endemic countries with 95,000 deaths. Early detection followed by prompt fluid and electrolyte replacement can reduce the case fatality ratio significantly. Improvements in water systems, sanitation and hygiene have effectively eliminated the transmission of cholera in high-income countries and reduced transmission in some developing nations. However, an estimated 1.8 billion are still at risk for cholera due to lack of potable water, inadequate sanitation and hygiene. Interventions focusing on hygiene in conjunction with proper disposal and treatment of sewage and provision of safe drinking water are likely to be effective in preventing the recurrence of cholera. Lastly, the use of current oral vaccines in endemic settings in combination with WASH interventions may be an effective approach to prevent and reduce the spread of cholera infection.

Salvage stereotactic radiosurgery for recurrent glioblastoma multiforme with prior radiation therapy.

BACKGROUND: Glioblastoma multiforme (GBM) carries a poor prognosis with high recurrence rates. Salvage stereotactic radiosurgery (SRS) may be an effective treatment option. METHODS: We retrospectively reviewed 34 patients (41 lesions) treated with salvage SRS for recurrent GBM between 2004 and 2012. Initial surgical treatments were gross total resection (58%), subtotal resection (STR) (24%), and biopsy (18%). All patients were treated with prior radiation therapy. Recurrent disease was treated with salvage SRS with a median dose and fractions of 23.4 Gy (range, 12-30) and 3 (range, 1-3), respectively. Cox proportional hazards regression was conducted to establish predictive factors (P ≤ 0.05) Results: Median follow-up from salvage SRS was 10.8 months (interquartile range [IQR], 7.0-15.6). The median time from initial radiation therapy to salvage SRS was 13.7 months (IQR, 2.9-25.0). The 6- and 12-month overall survival from salvage SRS were 84.9% and 42.5%, respectively. On univariate analysis, STR was associated with inferior survival from salvage SRS (P ≤ 0.05). The 6- and 12-month local control (LC) estimates were 63.1% and 16.4%, respectively. On univariate analysis, higher biological effective dose and prior temozolomide were associated with superior LC. Concerning toxicity, there were 4 (12%) grade 2 and 1 (3%) grade 3 adverse events within this patient series. No grade 4 or grade 5 toxicities were observed. CONCLUSION: Our outcomes suggest that SRS is a feasible treatment option with acceptable salvage survival rates, given the poor prognosis of this disease.

Tumor bed radiosurgery following resection and prior stereotactic radiosurgery for locally persistent brain metastasis.

PURPOSE: Despite advances in multimodality management of brain metastases, local progression following stereotactic radiosurgery (SRS) can occur. Often, surgical resection is favored, as it frequently provides immediate symptom relief as well as pathological characterization of any residual tumor. Should the pathological specimen contain viable tumor cells, further radiation therapy is an option to sterilize the tumor bed. We evaluated the use of repeat SRS (rSRS) in lieu of whole-brain radiation therapy (WBRT) as a means of improving local control (LC) while minimizing potential toxicity and dose to the normal brain. MATERIALS/METHODS: A retrospective review was performed to identify patients with brain metastases who underwent SRS and then surgical resection for locally recurrent or persistent disease. From 2004 to 2014, 13 consecutive patients or 15 lesions were treated with rSRS after resection, either post-operatively to the tumor bed (n = 10, 66.6%) or after a second local recurrence (n = 5, 33.3%). LC, distant brain failure (DBF), and radiation toxicity were determined using patient records, RECIST criteria v1.1, and CTCAE v4.03. RESULTS: At a median follow-up interval of 9.0 months (range 1.8-54.9 months) from time of rSRS, five patients remain alive. Following rSRS, 13 of the 15 (86.6%) lesions were locally controlled with an estimated 100% LC at 6 months and 75% LC at 1 year. However, 11 of the 15 (73.3%) treated lesions developed DBF after rSRS with 3 of 13 patients proceeding to WBRT. Two of 15 (13.3%) resulted in either grade 2 radionecrosis with grade 3 seizures or grade 3 radionecrosis. CONCLUSION: Repeat SRS represents a potential salvage therapy for patients with locally recurrent brain metastases, providing additional tumor control with acceptable toxicity, even in the setting of prior SRS and surgical resection. rSRS may be reasonable to use as an alternative to WBRT in this setting.

Designing the Expanded Programme on Immunisation (EPI) as a service: Prioritising patients over administrative logic.

Expanded Programme on Immunisation (EPI) vaccination rates remain well below herd immunity in regions of many countries despite huge international resources devoted to both financing and access. We draw upon service marketing theory, organisational sociology, development anthropology and cultural consumer research to conduct an ethnographic study of vaccination delivery in Jimma Zone, Ethiopia - one such region. We find that Western public health sector policies are dominated by an administrative logic. Critical failures in delivery are produced by a system that obfuscates the on-the-ground problems that mothers face in trying to vaccinate their children, while instead prioritising administrative processes. Our ethnographic analysis of 83 mothers who had not vaccinated their children reveals key barriers to vaccination from a 'customer' perspective. While mothers value vaccination, it is a 'low involvement' good compared to the acute daily needs of a subsistence life. The costs imposed by poor service - such as uncaring staff with class hostilities, unpredictable and missed schedules and long waits - are too much and so they forego the service. Our service design framework illuminates specific service problems from the mother's perspective and points towards simple service innovations that could improve vaccination rates in regions that have poor uptake.

Improved hematopoiesis in GS-nitroxide (JP4-039)-treated mouse long-term bone marrow cultures and radioresistance of derived bone marrow stromal cell lines.

AIM: To determine if the small-molecule radioprotector GS-nitroxide, JP4-039, improved hematopoiesis in long-term bone marrow cultures (LTBMCs), explanted marrow from in vivo drug-treated C57BL/6NTac mice was maintained in JP4-039 for 25 weeks. Hematopoietic cell production and radiobiology of derived stromal cell lines was measured. MATERIALS AND METHODS: Groups of LTBMCs were established from mouse groups. Stromal cell lines were established from the adherent layer of JP4-039-treated and untreated control groups. RESULTS: LTBMCs maintained in JP4-039 exhibited increased production of total non-adherent and 7-day and 14-day hematopoietic colony-forming cells. Stromal cell lines derived from JP4-039-treated cultures were radioresistant in vitro, demonstrated a distinct squamous/epithelial morphology and overexpressed Nrf2, Ctgf, Lox, Tlr1, collagen 1a, Brd3, and Brd4. CONCLUSION: Chronic treatment of bone marrow cultures and derived stromal cell lines with JP4-039 was non-toxic, and conferred resistance to oxidative stress.

Hyperbaric oxygen protects from sepsis mortality via an interleukin-10-dependent mechanism.

OBJECTIVE: This study was performed to determine whether hyperbaric oxygen (HBO2) therapy is protective in cecal ligation and puncture (CLP)-induced sepsis and if protection is dependent on oxygen dosing. We also wished to determine whether HBO2 affected bacterial clearance or altered macrophage production of interleukin-10 (IL-10)s in the setting of CLP sepsis. Finally, we wished to determine whether the mechanism of HBO2 protection in sepsis was dependent on IL-10 production. DESIGN: Prospective, experimental study. SETTING: University experimental research laboratory. SUBJECTS: C57BL/6 and C57BL/6 IL-10 mice. INTERVENTIONS: Sepsis was induced by CLP. Mice were randomized to receive a 1.5-hr HBO2 treatment at either 1, 2.5, or 3 atmospheres absolute every 12 hrs or HBO2 at 2.5 atmospheres absolute every 24 hrs. Mice were also harvested at 24 hrs for determination of bacterial load and isolation and study of CD11b peritoneal macrophages. MEASUREMENTS AND MAIN RESULTS: Survival was monitored for 100 hrs after CLP +/- HBO2 treatment. HBO2 significantly improved survival when administered at 2.5 atmospheres absolute every 12 hrs. Other treatment schedules were not protective, and treatment at 3.0 atmospheres absolute significantly worsened survival outcome. Bacterial load was significantly reduced in splenic homogenates but not peritoneal fluid at 24 hrs. Macrophages isolated from HBO2-treated mice demonstrated enhanced IL-10 secretion in response to lipopolysaccharide as compared with CLP controls. Mice genetically deficient in IL-10 expression treated with HBO2 at 2.5 atmospheres absolute every 12 hrs were not protected from CLP-induced mortality. CONCLUSION: HBO2 may be protective in CLP sepsis within a window of oxygen dosing. The mechanism of HBO2 protection may be potentially linked in part to expression of IL-10, as peritoneal macrophages demonstrated enhanced IL-10 expression and IL-10 mice were not protected by HBO2 treatment.

Hyperbaric oxygen reduces acetaminophen toxicity and increases HIF-1alpha expression.

OBJECTIVES: To investigate the effect of hyperbaric oxygen (HBO2) on acetaminophen (APAP)-induced hepatotoxicity. The authors further evaluated the effects of APAP poisoning and HBO2 on the expression and function of hypoxia-inducible factor 1-alpha (HIF-1alpha) in an effort to further describe the mechanisms of APAP-induced hepatotoxicity. In vitro assays were performed to better understand the effects of HBO2 on HIF-1alpha function. METHODS: In vivo, four groups of C57BL/6 mice were treated as follows: APAP only, APAP followed by HBO2, HBO2 only, and untreated shams. Plasma alanine aminotransferase activity was measured, and hepatic HIF-1alpha induction was determined by Western blot. In vitro, cultured HEP G2 hepatocytes were exposed to HBO2, hypoxia (2.5% O2), or normoxia. HIF-1alpha DNA-binding and transcriptional activity were assessed. RESULTS: Alanine aminotransferase activity was reduced in the APAP+HBO2 group (2,606 IU/L +/- 4,080; vs. APAP: 6,743 +/- 3,397, p = 0.01 at 6 hours). APAP-only, HBO2-only, and APAP+HBO2 treatments all increased HIF-1alpha expression relative to shams (p = 0.02, p = 0.02, and p < 0.01, respectively). HBO2 increased HIF-1alpha DNA binding 5.7 (+/- 1.2)-fold relative to controls (p < 0.01); however, a parallel increase in HIF functional transcriptional activity did not occur. CONCLUSIONS: Hyperbaric oxygen reduced early APAP-induced hepatocellular injury. APAP poisoning increases HIF-1alpha protein levels and functional activity. HBO2 increases HIF-1alpha protein levels and DNA binding without a corresponding increase in transcriptional activity.

How global brands compete.

It's time to rethink global branding. More than two decades ago, Harvard Business School professor Theodore Levitt argued that corporations should grow by selling standardized products all over the world. But consumers in most countries had trouble relating to generic products, so executives instead strove for global scale on backstage activities such as production while customizing product features and selling techniques to local tastes. Such "glocal" strategies now rule marketing. Global branding has lost more luster recently because transnational companies have been under siege, with brands like Coca-Cola and Nike becoming lightning rods for antiglobalization protests. The instinctive reaction of most transnational companies has been to try to fly below the radar. But global brands can't escape notice. In fact, most transnational corporations don't realize that because of their power and pervasiveness, people view them differently than they do other firms. In a research project involving 3,300 consumers in 41 countries, the authors found that most people choose one global brand over another because of differences in the brands'global qualities. Ratherthan ignore the global characteristics of their brands, firms must learn to manage those characteristics. That's critical, because future growth for most companies will likely come from foreign markets. Consumers base preferences on three dimensions of global brands--quality (signaled by a company's global stature); the cultural myths that brands author; and firms' efforts to address social problems. The authors also found that it didn't matter to consumers whether the brands they bought were American--a remarkable finding considering that the study was conducted when anti-American sentiment in many nations was on the rise.