Smartphone microendoscopy for high resolution fluorescence imaging

High resolution optical endoscopes are increasingly used in diagnosis of various medical conditions of internal organs, such as the gastrointestinal tracts, but they are too expensive for use in resource-poor settings. On the other hand, smartphones with high resolution cameras and Internet access have become more affordable, enabling them to diffuse into most rural areas and developing countries in the past decade. In this letter we describe a smartphone microendoscope that can take fluorescence images with a spatial resolution of 3.1 {\mu}m. Images collected from ex vivo, in vitro and in vivo samples using the device are also presented. The compact and cost-effective smartphone microendoscope may be envisaged as a powerful tool for detecting pre-cancerous lesions of internal organs in low and middle income countries.Comment: 4 pages, 4 figure

Noninvasive monitoring of tumor oxygenation response to anti-hypoxia drug using near- infrared spectroscopy

Tumor hypoxia is a characteristic feature of solid tumors, which will lead to enhanced tumor metastasis and resistance to radiation therapy. Many strategies have been proposed to increase the overall functional oxygenation and radiosensitivity of hypoxic tumors, by delivering more oxygen to the hypoxic tumor or reducing the oxygen consumption within the tumor by using anti-hypoxia agents. Preliminary data indicated that FDA approved drug papaverine could effectively reduce the mitochondrial oxygen consumption rate of human lung tumor cells (A549) in vitro and thus can reduce hypoxia-induced radiation resistance. However, the real-time tumor oxygenation response to papaverine in vivo remains to be characterized, and the optimal temporal window for delivery of radiation after anti-hypoxia therapy requires to be determined. Optical spectroscopy, particularly frequency-domain near-infrared spectroscopy (FD-NIRS), provides a new noninvasive approach for continuously monitoring tumor hypoxia in vivo. In this study, we have developed a side-firing fiber optic surface sensor and an FD-NIRS instrument with four laser wavelengths for quantifying tumor oxygenation in response to papaverine in human tumor xenograft models. Nude mice bearing subcutaneous A549 xenografts on the flank were used for tumor hypoxia study. Heathy nude mice without tumors were assigned as a control. The side-firing surface sensor was attached to the skin above the tumor or the muscle tissue on the flank of the animals. All animals were administrated with a constant flow of compressed air mixed with isoflurane throughout the experiments. 30-minute baseline measurement prior to injection, followed by 120-minute continuous measurement after injection were conducted for each animal. Intravenous tail injection of papaverine at 2 mg/kg or the same volume of 0.9% saline solution was applied to the animals. Typical results are presented in Fig. 1. The baseline measurement became stable with a small fluctuation of ±2% in ~15 minutes when the animals became fully anesthetized and breathed regularly. The slightly increase in tissue oxygenation (SO2) prior to injection was mainly due to injection preparing procedures like tail heating and injecting attempts. Significant increase in SO2 was observed for A549 tumors in response to papaverine (from ~48% to~57%). SO2 reached the highest reading within 20 minutes after papaverine injection and remained at the highest for 30 minutes. In comparison, the difference in SO2 between the post papaverine injection and the baseline readings for muscle tissue was small. Similarly, the change in SO2 after saline injection for tumor-bearing mice was not obvious. Please click Additional Files below to see the full abstract

A Dual-modality Smartphone Microendoscope for Quantifying the Physiological and Morphological Properties of Epithelial Tissues

We report a nonconcurrent dual-modality fiber-optic microendoscope (named SmartME) that integrates quantitative diffuse reflectance spectroscopy (DRS) and high-resolution fluorescence imaging (FLI) into a smartphone platform. The FLI module has a spatial resolution of ~3.5 µm, which allows the determination of the nuclear-cytoplasmic ratio (N/C) of epithelial tissues. The DRS has a spectral resolution of ~2 nm and can measure the total hemoglobin concentration (THC) and scattering properties of epithelial tissues with mean errors of 4.7% and 6.9%, respectively, which are comparable to the errors achieved with a benchtop spectrometer. Our preliminary in vivo studies from a single healthy human subject demonstrate that the SmartME can noninvasively quantify the tissue parameters of normal human oral mucosa tissues, including labial mucosa tissue, gingival tissue, and tongue dorsum tissue. The THCs of the three oral mucosa tissues are significantly different from each other (p ≤ 0.003). The reduced scattering coefficients of the gingival and labial tissues are significantly different from those of the tongue dorsum tissue (p \u3c 0.001) but are not significantly different from each other. The N/Cs for all three tissue types are similar. The SmartME has great potential to be used as a portable, cost-effective, and globally connected tool to quantify the THC and scattering properties of tissues in vivo

Lymph node yield less than 12 is not a poor predictor of survival in locally advanced rectal cancer after laparoscopic TME following neoadjuvant chemoradiotherapy

PurposePrevious studies have confirmed that neoadjuvant chemoradiotherapy (nCRT) may reduce the number of lymph nodes retrieved in rectal cancer. However, it is still controversial whether it is necessary to harvest at least 12 lymph nodes for locally advanced rectal cancer (LARC) patients who underwent nCRT regardless of open or laparoscopic surgery. This study was designed to evaluate the relationship between lymph node yield (LNY) and survival in LARC patients who underwent laparoscopic TME following nCRT.MethodsPatients with LARC who underwent nCRT followed by laparoscopic TME were retrospectively analyzed. The relationship between LNY and survival of patients was evaluated, and the related factors affecting LNY were explored. To further eliminate the influence of imbalance of clinicopathological features on prognosis between groups, propensity score matching was conducted.ResultsA total of 257 consecutive patients were included in our study. The median number of LNY was 10 (7 to 13) in the total cohort. There were 98 (38.1%) patients with 12 or more lymph nodes harvested (LNY ≥12 group), and 159 (61.9%) patients with fewer than 12 lymph nodes retrieved (LNY <12 group). There was nearly no significant difference between the two groups in clinicopathologic characteristics and surgical outcomes except that the age of LNY <12 group was older (P<0.001), and LNY <12 group tended to have more TRG 0 cases (P<0.060). However, after matching, when 87 pairs of patients obtained, the clinicopathological features were almost balanced between the two groups. After a median follow-up of 65 (54 to 75) months, the 5-year OS was 83.9% for the LNY ≥12 group and 83.6% for the LNY <12 group (P=0.893), the 5-year DFS was 78.8% and 73.4%, respectively (P=0.621). Multivariate analysis showed that only patient age, TRG score and ypN stage were independent factors affecting the number of LNY (all P<0.05). However, no association was found between LNY and laparoscopic surgery-related factors.ConclusionsFor LARC patients who underwent nCRT followed by laparoscopic TME, the number of LNY less than 12 has not been proved to be an adverse predictor for long-term survival. There was no correlation between LNY and laparoscopic surgery-related factors

Clinicopathological characteristics and treatment outcome of resectable gastric cancer patients with small para-aortic lymph node

BackgroundResectable gastric cancer (GC) patients with small para-aortic lymph node (smaller than 10mm in diameter, sPAN) were seldom reported, and existing guidelines did not provide definite treatment recommendation for them.MethodsA total of 667 consecutive resectable GC patients were enrolled. 98 patients were in the sPAN group, and 569 patients without enlarged para-aortic lymph node were in the nPAN group. Standard D2 lymphadenectomy was performed. Neoadjuvant and adjuvant chemotherapy were administrated according to the cTNM and pTNM stage, respectively. Clinicopathological features and prognosis were compared between these two groups.ResultsThe median size of sPAN was 6 (range, 2−9) mm and the distribution was prevalent in No. 16b1. cN stage (p=0.001) was significantly related to the presence of sPAN. sPAN was both independent risk factor for OS (p=0.031) and RFS (p=0.046) of all patients. The prognosis of patients with sPAN was significantly worse than that of patients with nPAN (OS: p=0.008; RFS: p=0.007). Preoperative CEA and CA19-9 were independent risk factors for prognosis of patients with sPAN. Furthermore, patients in the sPAN group with normal CEA and CA19-9 exhibited acceptable prognosis (5-year OS: 67%; RFS: 64%), while those with elevated CEA or CA19-9 suffered significantly poorer prognosis (5-year OS: 17%; RFS: 17%) than patients in the nPAN group (5-year OS: 64%; RFS 62%) (both p < 0.05).ConclusionsStandard D2 lymphadenectomy should be considered a valid approach for GC patients with sPAN associate to normal preoperative CEA and CA19-9 levels. Patients with sPAN associated to elevated CEA or CA19-9 levels could benefit from a multimodal approach: neoadjuvant chemotherapy; radical surgery with D2 plus lymph nodal dissection extended to No. 16 station

Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

The New Delhi Metallo-β-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomes potentially a major global health threat

Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase

The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes

Dual-modality Smartphone-based Fiber-optic Microendoscope System for Early Detection of Cervical Neoplasia

Cervical cancer remains the leading cause of death for women in low middle-income countries (LMICs), where the incidence and mortality of cervical cancer are disproportionately high. Due to the poor medical conditions and lack of resources, the benefits of early screening methods such Pap smear and HPV test have yet to be realized in these areas. The more viable screening option - visual inspection with acetic acid (VIA) is relatively easier to implement and lower in cost. However, the effectiveness of VIA on the early detection of cervical cancer is still in question because of its low specificity, which may lead to many unnecessary follow-up diagnoses and treatments. Optical endoscopy is a powerful tool for detecting pre-cancerous changes in the epithelial tissue of the cervix. In this dissertation, we report the design and development of a dual-modality fiber-optic microendoscope system (SmartME) that integrates high-resolution fluorescence imaging (FLI) and quantitative diffuse reflectance spectroscopy (DRS) onto a smartphone platform. A smartphone App has also been developed to control the SmartME, pre-process the data, and wirelessly communicate with a remote server where the image and data are processed to extract diagnostically meaningful tissue parameters. The SmartME device has been thoroughly tested and calibrated. The FLI has a spatial resolution of ~3.5 µm, which allows imaging of subcellular organelles and determining the nuclear-cytoplasmic ratio of epithelial tissues. The DRS has a spectral resolution of 2 nm and is capable of measuring optical properties of epithelial tissues with a mean error of ~5%, which is comparable to what can be achieved with a commercial spectrometer. The feasibility of the device in measuring biological samples has been verified ex vivo using monolayer cervical cancer cells, tumor tissue from xenograft solid tumor models and other normal tissues. In vivo study on healthy human oral mucosa tissues has demonstrated that the SmartME can noninvasively quantify the tissue parameters and distinguish between different tissue types. The SmartME may provide a compact, cost-effective, and globally connected solution for early detection of neoplastic changes in epithelial tissues

Clinical significance of circulating immune cells in left- and right-sided colon cancer

Background Left-sided and right-sided colon cancers (LCCs and RCCs, respectively) differ in their epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and prognosis. Notably, immune response gene expression profiles have been shown to differ between patients with LCC and patients with RCC. The immune system plays an important role in tumor immunosurveillance, and there is increasing evidence that peripheral blood immune cells have a profound influence on tumor prognosis. This study aimed to determine the clinical significance of circulating immune cells with respect to colon tumor locations. Methods Different types of circulating immune cells were separated and analysed based on their surface markers by flow cytometry. We compared the numbers of dendritic cells (DCs) and T cell subsets in the peripheral blood of 94 patients with RCC or LCC and analysed the proportions of these immune cells in relation to tumor stage, tumor differentiation and lymphatic metastasis. Results We show that at later tumor stages, patients with LCC had higher levels of circulating myeloid DCs (P = 0.049) and plasmacytoid DCs (P = 0.018) than patients with RCC. In poorly differentiated tumors, LCC patients had significantly higher amount of plasmacytoid DCs (P = 0.036), CD4+ memory T (Tm) cells (P = 0.012), CD4+ T cells (P = 0.028), Tm cells (P = 0.014), and regulatory T cells (P = 0.001) than RCC patients. The levels of circulating CD4+ T cells, Tm cells and CD4+ Tm cells were significantly elevated at later stages in patients with LCC or RCC, while these cells decreased in poorly differentiated tumors in patients with RCC. Moreover, CD4+ Tm cell and CD4+ T cell levels are significantly associated with lymph node metastasis in patients with LCC and RCC. Discussion Circulating immune cells were associated with tumor location, tumor stage and tumor differentiation, and can be used to predict lymphatic metastasis in patients with colon cancer. This variation in systemic immunity could contribute to the differential prognosis of patients with colon cancer

Transient Tear Film Dysfunction after Cataract Surgery in Diabetic Patients.

Diabetes mellitus is an increasingly common systemic disease. Many diabetic patients seek cataract surgery for a better visual acuity. Unlike in the general population, the influence of cataract surgery on tear film function in diabetic patients remains elusive. The aim of this study was to evaluate the tear function in diabetic and nondiabetic patients following cataract surgery.In this prospective, interventional case series, 174 diabetic patients without dry eye syndrome (DES) and 474 age-matched nondiabetic patients as control who underwent phacoemulsification were enrolled at two different eye centers between January 2011 and January 2013. Patients were followed up at baseline and at 7 days, 1 month, and 3 months postoperatively. Ocular symptom scores (Ocular Surface Disease Index, OSDI) and tear film function including tear film stability (tear film break-up time, TBUT), corneal epithelium integrity (corneal fluorescein staining, CFS), and tear secretion (Schirmer's I test, SIT) were evaluated.In total, 83.9% of the diabetic patients (146 cases with 185 eyes) and 89.0% of the nondiabetic patients (422 cases with 463 eyes) completed all check-ups after the interventions (P = 0.095). The incidence of DES was 17.1% in the diabetic patients and 8.1% in the nondiabetic patients at 7 days after cataract surgery. In the diabetic patients, the incidence of DES remained 4.8% at 1 month postoperatively and decreased to zero at 3 months after surgery. No DES was diagnosed in nondiabetic patients at either the 1-month or 3-month follow-up. Compared with the baseline, the diabetic patients had worse symptom scores and lower TBUT values at 7 days and 1 month but not at 3 months postoperatively. In the nondiabetic patients, symptom scores and TBUT values had returned to preoperative levels at 1-month check-up. CFS scores and SIT values did not change significantly postoperatively in either group (P = 0.916 and P = 0.964, respectively).Diabetic patients undergoing cataract surgery are prone to DES. Ocular symptoms and tear film stability are transiently worsened in diabetic patients and are restored more slowly than those in nondiabetic patients