An interspecific linkage map of SSR and intronic polymorphism markers in tomato

Despite the collection and availability of abundant tomato genome sequences, PCR-based markers adapted to large scale analysis have not been developed in tomato species. Therefore, using public genome sequence data in tomato, we developed three types of DNA markers: expressed sequence tag (EST)-derived simple sequence repeat (SSR) markers (TES markers), genome-derived SSR markers (TGS markers) and EST-derived intronic polymorphism markers (TEI markers). A total of 2,047 TES, 3,510 TGS and 674 TEI markers were established and used in the polymorphic analysis of a cultivated tomato (Solanum lycopersicum) ‘LA925’ and its wild relative Solanum pennellii ‘LA716’, parents of the Tomato-EXPEN 2000 mapping population. The polymorphic ratios between parents revealed by the TES, TGS and TEI markers were 37.3, 22.6 and 80.0%, respectively. Those showing polymorphisms were used to genotype the Tomato-EXPEN 2000 mapping population, and a high-density genetic linkage map composed of 1,433 new and 683 existing marker loci was constructed on 12 chromosomes, covering 1,503.1 cM. In the present map, 48% of the mapped TGS loci were located within heterochromatic regions, while 18 and 21% of TES and TEI loci, respectively, were located in heterochromatin. The large number of SSR and SNP markers developed in this study provide easily handling genomic tools for molecular breeding in tomato. Information on the DNA markers developed in this study is available at http://www.kazusa.or.jp/tomato/

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

A comparison between SARS-CoV-2 and Gram-negative bacte- 1 ria-induced hyperinflammation and sepsis

Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which rank among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients "mimics bacterial sepsis". Furthermore, the immune response to SARS-CoV-2 was described by others as "mirror image of sepsis". Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection is frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. In the present review, we will analyze similarities and differences between COVID-19 and sepsis at the pathophysiological, epidemiological, and molecular levels

Mechanism of Hbγ-35-induced an increase in the activation of the human immune system by endotoxins

Endotoxins (LPS) are highly potent immune stimulatory molecules and are mainly known for triggering Gram-negative sepsis. However, besides their toxic effects, this stimulatory function may be advantageous, for example when used as an adjuvant during vaccination. Thus, there is always a narrow range between the useful wake-up of the immune system and its overwhelming reaction, which can lead to diseases like sepsis. This raises the question of which conformational properties are responsible for making the LPS aggregates more or less potent. As described previously, the size, type and form of LPS aggregates play a major role in their immune stimulatory activity. In this study we investigate the role of these parameters. On the one hand, we use a peptide (Pep19-2.5; Aspidasept) that causes a change of the LPS aggregate structure into a less toxic state; on the other hand, we use a potent immune stimulating peptide (Hbγ-35), leading to higher toxicity. We have found opposing effects on LPS aggregate conformations allowing a better understanding of the processes of immune stimulation.Peer Reviewe

Achievement of hearing preservation in the presence of an electrode covering the residual hearing region

CONCLUSIONS: With full insertion with a long electrode, hearing preservation can be achieved even in the presence of a long electrode covering the residual hearing region. OBJECTIVES: Advances in developing new atraumatic concepts of electrode design as well as surgical technique have enabled hearing preservation after cochlear implantation surgery, and EAS (electric acoustic stimulation) accompanied with hearing preservation is a new trend for patients with residual hearing at the lower frequencies. However, full insertion with a long/medium electrode and hearing preservation is still a challenging field that calls for discussion. METHOD: In this study, round window insertion, an atraumatic electrode, and dexamethasone administration were used and atraumaticity (hearing preservation and conservation of vestibular function) was evaluated with full insertion of the electrode. RESULTS: Postoperative evaluation after full insertion of the electrodes showed that hearing at low frequencies was well preserved in all five cases. Combined postoperative imaging with the referential tonotopic map confirmed achievement of full insertion and indicated the corresponding frequencies and the depth of the electrode. Achievement of atraumaticity of round window insertion in the present cases was confirmed from the viewpoint of the minimal drilling time as well as the preserved vestibular function