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Diabetes mellitus is a rapidly rising metabolic disorder with important systemic complications. Global figures have demonstrated the prevalence of diabetes mellitus has almost quadrupled from 108 million in 1980 to 422 million in 2014, with a current prevalence of over 525 million. Of the male sexual dysfunction resulting from diabetes mellitus, significant focus is afforded to erectile dysfunction. Nevertheless, ejaculatory dysfunction constitutes important sexual sequelae in diabetic men, with up to 35%-50% of men with diabetes mellitus suffering from ejaculatory dysfunction. Despite this, aspects of its pathophysiology and treatment are less well understood than erectile dysfunction. The main disorders of ejaculation include premature ejaculation, delayed ejaculation, anejaculation and retrograde ejaculation. Although ejaculatory dysfunction in diabetes mellitus can have complex multifactorial aetiology, understanding its pathophysiological mechanisms has facilitated the development of therapies in the management of ejaculatory dysfunction. Most of our understanding of its pathophysiology is derived from diabetic animal models; however, observational studies in humans have also provided useful information in elucidating important associative factors potentially contributing to ejaculatory dysfunction in diabetic men. These have provided the potential for more tailored treatment regimens in patients depending on the ejaculatory disorder, other co-existing sequelae of diabetes mellitus, specific metabolic factors as well as the need for fertility treatment. However, evidence for treatment of ejaculatory dysfunction, especially delayed ejaculation and retrograde ejaculation, is based on low-level evidence comprising small sample-size series and retrospective or cross-sectional studies. Whilst promising findings from large randomised controlled trials have provided strong evidence for the licensed treatment of premature ejaculation, similar robust studies are needed to accurately elucidate factors predicting ejaculatory dysfunction in diabetes mellitus, as well as for the development of pharmacotherapies for delayed ejaculation and retrograde ejaculation. Similarly, more contemporary robust data are required for fertility outcomes in these patients, including methods of sperm retrieval and assisted reproductive techniques in retrograde ejaculation.

Erectile dysfunction is associated with diabetes mellitus with an estimated prevalence of 52.5% in the diabetic population. The first-line therapy for erectile dysfunction is phosphodiesterase type 5 inhibitors, but data suggest that diabetic men may be less responsive than non-diabetic men. Thus, other treatments, including intracavernosal injections, intraurethral prostaglandin, vacuum erection devices and penile prosthetic surgery, should be considered in management of diabetic men with erectile dysfunction refractory to phosphodiesterase type 5 inhibitors. Furthermore, combination therapy of phosphodiesterase type 5 inhibitors and other oral treatments such as arginine or l-carnitine may have synergistic effects resulting in better outcomes. In addition, there are novel therapies such as low-intensity shockwave therapy and stem-cell therapy, which may also be effective in targeted treatment modalities. Furthermore, studies suggest that erectile dysfunction can be improved by targeting concurrent comorbidities or metabolic diseases such as depression, hypertension, hypogonadism, and dyslipidaemia. We present an evidence-based narrative review focusing on the management of erectile dysfunction in diabetic men who have not responded to phosphodiesterase type 5 inhibitors.Both clinicians and patients should be aware of the different management options in diabetic patients who have not responded to phosphodiesterase type 5 inhibitors.

We present an analytical treatment of ultra-short pulses propagating in an optical fiber in the strong nonlinearity regime, in which the interaction between self-phase modulation (SPM) and group-velocity dispersion (GVD) substantially broadens the input spectrum. Supported by excellent agreement with the simulation results, these analytical solutions provide a convenient and reasonable accurate estimation of the peak position of the outermost spectral lobes as well as the full width at half maximum of the broadened spectrum. We show that our unified solutions are valid for either Gaussian pulse or hyperbolic secant pulse propagating inside an optical fiber with positive or negative GVD. Our findings shed light on the optimization of SPM-enabled spectral broadening in various applications.

Infertility affects 15% of couples worldwide and in approximately 50% of cases the cause is secondary to an abnormality of the sperm. However, treatment options for male infertility are limited and empirical use of hormone stimulation has been utilised. We review the contemporary data regarding the application of hormone stimulation to treat male infertility. There is strong evidence supporting the use of hormone stimulation in hypogonadotropic hypogonadism but there is inadequate evidence for all other indications.

Background: MET gene amplification is associated with poor prognosis in gastric cancer (GC) and gastroesophageal junction adenocarcinomas (GEJ). Savolitinib is a potent and highly selective oral MET tyrosine-kinase inhibitor. Here we reported the preliminary efficacy and safety from a phase 2 trial of savolitinib monotherapy in patients (pts) with MET-amplified advanced or metastatic GC/GEJ. (NCT04923932). Methods: Eligible pts had 2L+ GEJ or GC, with MET amplification and measurable lesions. Pts received savolitinib at 600 mg QD for body weight (BW) ≥50 kg, while 400 mg QD for BW Results: As of IA, 20 pts were enrolled for QD regimen. Demographics and clinical outcomes are shown in table 1. The mean relative dose intensity of 93.07%. Median duration of exposure was 2.09 months. Confirmed ORR by IRC was 45%, and reached 50% in 16 patients with MET GCN (high) while only 1 PR was observed in 4 patients with MET GCN (low). Duration of response rate at 4-month was 85.7% with median follow up time of 5.5 months. The most common Gr≥3 TRAE (≥5%) were platelet count decreased, hypersensitivity, anemia, neutropenia and hepatic function abnormal. In all pts, only 1 patient discontinued treatment due to grade 4 liver function abnormal (TRAE) and no patient died due to TRAE. Conclusion: Savolitinib monotherapy had manageable safety and showed promising efficacy in pts with MET-amplified GEJ or GC, particularly in pts with MET high GCN. BID regimen is being investigated to further evaluate the efficacy and safety of savolitinib in pts with MET high GCN. Table 1. Pts baseline characteristics and clinical efficacy Baseline Characteristics ITT in IA (n=20) Median age (min, max), yearsSex (male/female), nECOG (0/1/2)Median BMI (min, max), (kg/m2)Primary location of tumor (GC/GEJ)Tumor stage (IV)Prior line of therapy (1/2/≥3)MET GCN (high/low) 57.00 (39.5, 76.8)17/33/15/220.8 (14.9, 25.8)16/4205/10/516/4 Clinical Efficacy By IRC By Investigator Confirmed objective response rateDisease control rate4m-DoR rate,% (95% CI) 45%65%85.7 (33.4, 97.9) 40%55%71.4 (25.8, 92.0) Citation Format: Zhi Peng, Hua Wang, Baorui Liu, Huiting Xu, Zhenyang Liu, Tianshu Liu, Jun Zhang, Yuxian Bai, Ying Yuan, Tao Wu, Feng Ye, Qinghua Pan, Jufeng Wang, Enxiao Li, Diansheng Zhong, Yueyin Pan, Yanru Qin, Yan Yang, Yusheng Wang, Aiping Zhou, Yongshun Chen, Dianbao Zhang, Hongli Liu, Xiujuan Qu, Shubin Wang, Ning Liu, Jinsheng Wu, Wei Li, Kejun Nan, Hongming Pan, Jianming Xu, Chunmei Bai, Heling Liu, Jia Wei, Runzhi Chen, Rongrong Li, Wei Li, Jinghong Zhou, Hongyan Yin, Qian Xu, Songhua Fan, Yongxin Ren, Weiguo Su, Lin Shen. A multicenter Phase II study of savolitinib in patients with MET-amplified gastroesophogeal junction adenocarcinomas or gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT152.

Synthesis of programmable atom-like nanoparticles (PANs) with high valences and high yields remains a grand challenge. Here, a novel synthetic strategy of microfluidic galvanic displacement (μ-GD) coupled with microfluidic DNA nanoassembly is advanced for synthesis of single-stranded DNA encoder (SSE)-encoded PANs for reliable surface-enhanced Raman scattering (SERS) sensing. Notably, PANs with high valences (e.g., n-valence, n = 12) are synthesized with high yields (e.g., >80%) owing to the effective control of interfacial reactions sequentially occurring in the microfluidic system. On the basis of this, we present the first demonstration of a PAN-based automatic analytical platform, in which sensor construction, sample loading and on-line monitoring are carried out in the microfluidic system, thus guaranteeing reliable quantitative measurement. In the proof-of-concept demonstration, accurate determination of tetracycline (TET) in serum and milk samples with a high recovery close to 100% and a low relative standard deviation (RSD) less than 5.0% is achieved by using this integrated analytical platform., A novel synthetic strategy is presented for microfluidic preparation of programmable atom-like nanoparticles with high valences and high yields.

SPM-enabled spectral selection (SESS) constitutes a powerful fiber-optic technique to generate wavelength broadly tunable femtosecond pulses. In the current demonstration, the maximum tuning range is 400 nm and the energy conversion efficiency from the pump source to the outmost spectral lobes is ∼25%. In this submission, we apply the particle swarm optimization method to the generalized nonlinear Schrödinger equation to identify the optimal parameters that maximize both the tuning range and the conversion efficiency. We show that SESS in an optical fiber with the optimized dispersion can deliver SESS pulses tunable in one octave wavelength range and the conversion efficiency can be as high as 80%. We further show the feasibility of experimental implementation based on specially designed fibers or on-chip waveguides.

BackgroundErlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrated therapeutic efficacy against pancreatic cancer. However, acquired resistance to erlotinib in pancreatic cancer is widely observed, and the exact mechanisms have not been fully explored until now. We examined the role of circular RNA circ_0013587 in the acquired resistance to erlotinib in pancreatic cancer cells and explored the underlying mechanisms.MethodsWe selected erlotinib-resistant pancreatic cancer cells from the AsPC-1 cell line. The expression of circ_0013587 was examined by qRT-PCR assays. The effects of circ_0013587 on pancreatic cancer cell proliferation, invasion, and erlotinib resistance were assessed by cell functional assays. Bioinformatic analysis and dual-luciferase reporter assays identified circ_0013587 and E-cadherin as direct targets of miR-1227. Mouse xenograft models were employed to investigate the function of circ_0013587 in erlotinib resistance of tumors in vivo.ResultsCirc_0013587 expression was significantly reduced in erlotinib-resistant AsPC-1 cells. We found that increasing circ_0013587 levels in erlotinib-resistant AsPC-1 cells re-sensitized them, whereas reducing circ_0013587 levels in erlotinib-sensitive AsPC-1 cells made them resistant. Mechanically, circ_0013587 released E-cadherin from the suppression of miR-1227, leading to E-cadherin up-regulation. Rescue assays highlighted that circ_0013587 reversed erlotinib resistance in pancreatic cancer cells by increasing E-cadherin levels through reducing the expression of miR-1227. Furthermore, circ_0013587 overexpression sensitized erlotinib-resistant AsPC-1 cells to erlotinib in xenograft models.ConclusionsOur results demonstrated that down-regulation of circ_0013587 contributes to acquired resistance to erlotinib in pancreatic cancer cells through mediating the miR-1227/E-cadherin pathway and that circ_0013587 is a potential target molecular to overcome erlotinib resistance.

Pre-chirp managed amplification (PCMA) allows the generation of optical pulses with a duration well below 100 fs. However, the pulse peak power is limited to 30 times improvement in both pulse energy and peak power compared with current Yb-fiber PCMA systems.

Background Ex vivo and in vivo detection and imaging of adenosine triphosphate (ATP) is critically important for the diagnosis and treatment of diseases, which still remains challenges up to present. Results We herein demonstrate that ATP could be fluorescently detected and imaged ex vivo and in vivo. In particular, we fabricate a kind of fluorescent ATP probes, which are made of titanium carbide (TC) nanosheets modified with the ROX-tagged ATP-aptamer (TC/Apt). In the constructed TC/Apt, TC shows superior quenching efficiency against ROX (e.g., ~ 97%). While in the presence of ATP, ROX-tagged aptamer is released from TC surface, leading to the recovery of fluorescence of ROX under the 545-nm excitation. Consequently, a wide dynamic range from 1 μM to 1.5 mM ATP and a high sensitivity with a limit of detection (LOD) down to 0.2 μM ATP can be readily achieved by the prepared TC/Apt. We further demonstrate that the as-prepared TC/Apt probe is feasible for accurate discrimination of ATP in different samples including living cells, body fluids (e.g., mouse serum, mouse urine and human serum) and mouse tumor models. Conclusions Fluorescence detection and imaging of ATP could be readily achieved in living cells, body fluids (e.g., urine and serum), as well as mouse tumor model through a new kind of fluorescent ATP nanoprobes, offering new powerful tools for the treatment of diseases related to abnormal fluctuation of ATP concentration.

Outcomes in partial sternotomy for aortic root surgery: the new routine procedure?Running Head: Partial sternotomy for aortic root repair

OSA continuum 3(7), 1988-1998 (2020). doi:10.1364/OSAC.392981, We incorporate two techniques into pre-chirp managed amplification (PCMA) to achieve high-energy ultrashort pulses with the duration well below 100 fs. Numerical simulations confirmed by our experimental results demonstrate that seeding PCMA with circularly polarized pulses instead of linearly polarized pulses can increase the amplified pulse energy by 1.5 times. We also employ high-dispersion chirped mirrors to compress the amplified pulses with the throughput efficiency as high as 98%. These two techniques allow us to demonstrate an Yb-fiber PCMA system that emits 50-MHz, 47-fs pulses with 101.2-W average power., Published by OSA, Washington, DC

BACKGROUND: For metastatic colorectal cancer (mCRC) patients for whom at least 2 lines of previous standard therapies have failed, the prognosis is often unfavorable due to very limited subsequent treatment options. We sought to explore the efficacy of apatinib, an oral small-molecule vascular endothelial growth factor receptor-2 inhibitor, plus 5-fluorouracil (5-FU) as a third- or subsequent-line treatment for mCRC. METHODS: In this phase-II, single-arm, prospective study, the eligible patients had been histologically confirmed to have adenocarcinoma of the colon or rectum for which at least 2 previous regimens of standard therapies had failed. All the patients were treated with a daily dose of 250 mg of apatinib, in combination with capecitabine, Tegafur Gimeracil Oteracil Potassium Capsule (S-1), or 5-FU, until disease progression, unacceptable toxicity, or consent withdrawal. RESULTS: From June 2017 to April 2018, 16 patients were enrolled in this study. Among them, 4 achieved partial response, 7 had stable disease, and 5 had progression disease, resulting in an objective response rate of 25.00% [95% confidence interval (CI): 7.27–52.38%], and a disease control rate of 68.75% (95% CI: 41.34–88.98%). The median progression-free survival (PFS) was 4.83 months (95% CI: 2.17–8.90 months), and the median overall survival (OS) was 9.10 months (95% CI: 5.59–15.18 months). The common treatment-related adverse events (AEs) were hand-foot syndrome (56.25%), hypertension (37.50%), proteinuria (37.50%), gingival bleeding (18.75%) and abdominal pain (18.75%). Grade 3 AEs, including hand-foot syndrome (18.75%), hypertension (12.50%), and proteinuria (12.50%), were observed in 7 patients. CONCLUSIONS: The combination regimen of apatinib plus 5-FU had encouraging anti-tumor efficacy, and is a feasible third- or subsequent-line treatment option for mCRC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03210064.

MicroRNAs (miRNAs) are promising biomarkers for the early diagnosis of breast cancer. Yet, simultaneous achievement of rapid, sensitive and accurate detection of diverse miRNAs in clinical samples is still challenging due to the low abundance of miRNAs and the complex procedures of RNA extraction and separation. Herein, we develop an innovative three-dimensional (3D) surface-enhanced Raman scattering (SERS) holography sensing strategy for rapid, sensitive and multiplexed detection of human breast cancer-associated miRNAs. To establish a proof of concept, nine kinds of human breast cancer-associated miRNAs are isothermally amplified by Exonuclease (Exo) III enzyme, and the products could be spatially separated to corresponding sensing region on silicon SERS substrates. Each region has been modified with corresponding hairpin DNA probes, which are used to identify and quantify the miRNAs. Different DNA probes are labeled with different Raman reporters, which serve as “SERS tags” to incorporate spectroscopic information into computer-generated 3D SERS hologram within ~9 min. We demonstrate that 3D SERS holography chip not only achieves an ultrahigh sensitivity down to ~1 aM but also feature a high correlation with RT-qPCR in the detection of nine miRNAs in 30 clinical serum samples. This work provides a feasible tool to improve the diagnosis of breast cancer.

Post-pulse-compression is demanded to produce energetic few-cycle pulses. We propose pre-chirp-managed adiabatic soliton compression (ASC) in gas-filled pressure-gradient hollow-core fibers to suppress the detrimental pedestals and therefore significantly improve the compressed pulse quality. We show that two-stage ASC can compress 125 μJ, 130 fs pulses at 2 μm to a nearly two-cycle pulse 15 fs in duration. Our analytical analysis suggests that ASC is in favor of compressing pulses centered at a longer wavelength. As an example, a 280 μJ, 220 fs Gaussian pulse at 4 μm is compressed to 60 fs with minimal pedestals. We expect that the resulting high-quality, energetic few-cycle pulses will find important applications in high-field science.