Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas

xloma.fota13 shared this article with you from Inoreader Optimized EGFR blockade strategies in EGFR addicted gastroesophageal adenocarcinomas Via Clinical Cancer Research Online First Articles Purpose: Gastric and gastroesophageal adenocarcinomas (GEA) represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced GEA is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced GEA treated with anti-EGFR agents. Experimental Design: We performed analyses on 4 cohorts: IRCC (570 patients), FMI (9397 patients), COG (214 patients) and INT (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDXs). Results: The analysis of different GEA patient cohorts suggests that EGFR amplification drives aggressive behaviour and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy number gain and that co-amplification of other receptor tyrosine kinases or KRAS is associated with worse response. Pre-clinical trials performed on EGFR-amplified G EA PDX models revealed that the combination of an EGFR monoclonal antibody and an EGFR tyrosine kinase inhibitor was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR amplified non-responding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, co-treatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition. Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a monoclonal antibody as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Expression of the ace operon in Escherichia coli is triggered in response to growth rate-dependent flux-signal of ATP

xloma.fota13 shared this article with you from Inoreader Expression of the ace operon in Escherichia coli is triggered in response to growth rate-dependent flux-signal of ATP Via FEMS Microbiology Letters - current issue ABSTRACT The signal that triggers the expression of the ace operon and, in turn, the transition of central metabolism's architecture from acetogenic to gluconeogenic in Escherichia coli remains elusive despite extensive research both in vivo and in vitro. Here, with the aid of flux analysis together with measurements of the enzymic activity of isocitrate lyase (ICL) and its aceA-messenger ribonucleuc acid (mRNA) transcripts, we provide credible evidence suggesting that the expression of the ace operon in E. coli is triggered in response to growth rate-dependent threshold flux-signal of adenosine triphosphate (ATP). Flux analysis revealed that the shortfall in ATP supply observed a s the growth rate ($\mu $) diminishes from µmax to ≤ 0.43h−1 ($ \pm 0.02;n4)\ $is partially redressed by up-regulating flux through succinyl CoA synthetase. Unlike glycerol and glucose, pyruvate cannot feed directly into the two glycolytic ATP-generating reactions catalyzed by phosphoglycerokinase and pyruvate kinase. On the other hand, glycerol, which upon its conversion to D-glyceraldehyde, feeds into the phosphorylation and dephosphorylation parts of glycolysis including the substrate-level phosphorylation-ATP generating reactions, thus preventing ATP flux from dropping to the critical threshold signal required to trigger the acetate-diauxic switch until glycerol is fully consumed. The mRNA transcriptional patterns of key gluconeogenic enzymes, namely, ackA, acetate kinase; pta, phosphotransacetylase; acs, acetyl CoA syntheta se and aceA, ICL, suggest that the pyruvate phenotype is better equipped than the glycerol phenotype for the switch from acetogenic to gluconeogenic metabolism. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comprehensive analysis of allergen-specific IgE in COPD: mite-specific IgE specifically related to the diagnosis of asthma-COPD overlap

xloma.fota13 shared this article with you from Inoreader Comprehensive analysis of allergen-specific IgE in COPD: mite-specific IgE specifically related to the diagnosis of asthma-COPD overlap Via Allergy, Asthma & Clinical Immunology - Latest Articles Although the relationship between allergic sensitization and increased respiratory symptoms of chronic obstructive pulmonary disease (COPD) has been suggested, which allergen has a significant effect on COPD p... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cancers, Vol. 13, Pages 625: The Immune Microenvironment in Multiple Myeloma: Friend or Foe?

xloma.fota13 shared this article with you from Inoreader Cancers, Vol. 13, Pages 625: The Immune Microenvironment in Multiple Myeloma: Friend or Foe? Via Cancers Cancers, Vol. 13, Pages 625: The Immune Microenvironment in Multiple Myeloma: Friend or Foe? Cancers doi: 10.3390/cancers13040625 Authors: Raquel Lopes Joana Caetano Bruna Ferreira Filipa Barahona Emilie Arnault Carneiro Cristina João Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and su ppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Cocktail of carbohydrases from Aspergillus niger: an economical and eco-friendly option for biofilm clearance from biopolymer surfaces

xloma.fota13 shared this article with you from Inoreader Cocktail of carbohydrases from Aspergillus niger: an economical and eco-friendly option for biofilm clearance from biopolymer surfaces Via Applied and Industrial Microbiology Biofilm formation on both biotic and abiotic surfaces accounts for a major factor in spread of antimicrobial resistance. Due to their ubiquitous nature, biofilms are of great concern for environment as well as... View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Mutation patterns in recurrent and/or metastatic oropharyngeal squamous cell carcinomas in relation to human papillomavirus status

xloma.fota13 shared this article with you from Inoreader Mutation patterns in recurrent and/or metastatic oropharyngeal squamous cell carcinomas in relation to human papillomavirus status Via Cancer Medicine A subgroup of 13–25% of HPV‐driven (HPV+) OPSCC patients develop local or distant recurrence (LDR) and a severe course of disease similar to that of patients with HPV‐negative (HPV‐) OPSCC. Regarding the genes analyzed, we found that the HPV+OPSCC of patients with LDR carried a higher number of mutations than HPV+OPSCC of patients without LDR, with a similar mutation frequency as the HPV−OPSCC of LDR patients. Surprisingly, HPV−OPSCC of patients who did not develop LDR showed the highest number of mutations, suggesting that not the number but specific driver mutations are dominant factors for recurrence and that tumor‐specific neoantigens may play a role in a supportive antitumor immune response after therapy. Abstract Patients with HPV‐driven (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) have a significantly improved overall survival compared to patients with HPV‐negative (HPV−) OPSCC. Nevertheless, 13%–25% of patients with HPV+OPSCC develop local/distant recurrence (LDR) and have a course of disease similar to HPV−OPSCC. We hypothesize that HPV+OPSCCs of patients with LDR have a mutation frequency and pattern similar to HPV−OPSCCs, which is associated with severe outcome. We performed targeted next‐generation sequencing using a customized gene panel and compared data from 56 matched HPV+and HPV−OPSCC of patients with/without LDR regarding protein‐altering variants. Despite improved overall survival of patients with HPV+OPSCC, those who develop LDR show a strongly reduced survival rate that is similar or even worse compared to HPV−OPSCC patients. Overall, the number of mutations was similar in OPSCC of patients with and without LDR. In total and with respect to TP5 3, HPV−OPSCC had significantly more protein‐altering mutations than HPV+OPSCC. The number of mutations was similar in HPV−OPSCC of patients with and without LDR with the exception of FAT1, which was mutated more frequently in patients without LDR. In HPV+OPSCC, HRAS, PIK3R1, STK11 and TP63 were more frequently mutated in patients with LDR compared to patients without. HPV+OPSCC of patients with LDR have a similar mutation pattern as HPV−OPSCC, except TP53, which was mutated to a significantly lower extent. In conclusion, HPV−and HPV+OPSCC with LDR have similar mutation counts in the analyzed genes. We suspect that the number of mutations is not causal for disease progression, rather specific mutations could be important. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Comparison of efficacy, safety, patients’ quality of life, and doctors’ occupational stress between lenalidomide‐based and bortezomib‐based induction in patients with newly diagnosed multiple myeloma

xloma.fota13 shared this article with you from Inoreader Comparison of efficacy, safety, patients' quality of life, and doctors' occupational stress between lenalidomide‐based and bortezomib‐based induction in patients with newly diagnosed multiple myeloma Via Cancer Medicine Compared to PAD, RAD induction had a comparable efficacy and significantly better safety profile, improved quality of life for patients and reduced occupational stress for doctors. However, RAD had an effect on stem cell collection, which may need to be limited to 4 cycles to avoid irreversible damage to hematopoietic stem cells. Abstract Background In the new therapeutic era, comparisons between regimens containing lenalidomide and bortezomib are needed. Methods In this single‐center, prospective study, patients received four to six cycles of lenalidomide+liposomal doxorubicin+dexamethasone (RAD) or bortezomib+liposomal doxorubicin+dexamethasone (PAD) every 4 weeks, with subsequent autologous stem cell transplantation (ASCT) and maintenance therapy. We compared the efficacy, safety, patients' quality of life, and doctors' occupational stress between RAD and PAD induction in newly diagnosed MM patients. Results The complete response (CR) rate was comparable between the RAD and PAD groups after induction (30.8% vs. 32.0%, p = 0.92). Common adverse events, including infections, peripheral neuropathy, and gastrointestinal disturbances, were more frequent in the PAD group, while leukopenia and rashes were more common in the RAD group. Compared with PAD, RAD improved patients' quality of life more quickly and caused less occupational stress for doctors. However, only 31.6% of patients collected adequate CD34+ cells (≥2 × 106/kg) in the RAD group, which was significantly lower than that in the PAD group (95.5%, p < 0.001). The number of CD34+ cells collected was significantly higher in patients within three courses of RAD than in patients with four or five to six courses (14.18 ± 13.57 vs. 2.07 ± 2.42 vs. 1.51 ± 1.81 × 106/kg, p = 0.028). The median progression ‐free survival and overall survival of the two groups were not reached by the end of follow‐up. Conclusion Compared to PAD, RAD induction had comparable efficacy and a significantly better safety profile, improved quality of life for patients, and reduced occupational stress for doctors. However, RAD induction may need to be limited to four cycles to avoid irreversible damage to hematopoietic stem cells. Clinical trial registration This study was registered at www.chictr.org.cn (ChiCTR1900021558). View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.