pH sensing in skin tumors: Methods to study the involvement of GPCRs,acid-sensing ion channels and transient receptor potential vanilloid channels

Solid tumors exhibit an inversed pH gradient with increased intracellular pH (pH_i) and decreased extracellular pH (pH_e). This inside-out pH gradient is generated via sodium/hydrogen antiporter 1, vacuolar-type H + ATPases, monocarboxylate transporters, (bi)carbonate (co)transporters and carboanhydrases. Our knowledge on how pH_e-signals are sensed and what the respective receptors induce inside cells is scarce. Some pH-sensitive receptors (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A, possibly GPR31 and GPR151) and ion channels (acid-sensing ion channels ASICs, transient receptor potential vanilloid receptors TRPVs) transduce signals inside cells. As little is known on the expression and function of these pH sensors, we used immunostainings to study tissue samples from common and rare skin cancers. Our current and future work is directed towards investigating the impact of all the pH-sensing receptors in different skin tumors using cell culture techniques with selective knockdown/knockout (siRNA/CRISPR-Cas9). To study cell migration and proliferation, novel impedance-based wound healing assays have been developed and are used. The field of pH sensing in tumors and wounds holds great promise for the development of pH-targeting therapies, either against pH regulators or sensors to inhibit cell proliferation and migration.     

Interval breast cancer risk associations with breast density,family history and breast tissue aging

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first-degree family history by questionnaire, measured body mass index (BMI) and calculated age-adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age-adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer.     

Health Literacy,Knowledge on Cervical Cancer and Pap Smear and Its Influence on Pre-Marital Malay Muslim Women Attitude towards Pap Smear

Background: Cervical cancer is preventable. In Malaysia, women are found to have good awareness of the disease and yet, the Pap smear uptake is still poor. Measuring health literacy level could explain this discrepancy. This study aims to determine the relationship between health literacy, level of knowledge of cervical cancer and Pap smear with attitude towards Pap smear among women attending pre-marital course. Methods: A cross sectional study was performed in three randomly selected centres that organised pre-marital courses. All Malay Muslim women participants aged 18 to 40 years old were recruited while non-Malaysian, illiterate, and had hysterectomy were excluded. Validated self-administered questionnaires used were European Health Literacy Questionnaire (HLS-EU-Q16 Malay) and Knowledge and attitude towards Cervical Cancer and Pap Smear Questionnaire. The mean percentage score (mean± SD) was calculated, with higher scores showed better outcomes. Multiple linear regression was used to measure the relationship of independent variables with attitude towards Pap smear. Results: A total of 417 participants were recruited with a mean age of 24.9 ± 3.56 years old. Prevalence of awareness of cervical cancer was 91.6% (n=382, 95% CI: 89.0%, 94.2%) and mean percentage score was 74.7%±7.6. Prevalence of awareness of Pap smear was 59.0% (n=246, 95% CI: 54.2%, 63.8%) and mean percentage score was 80.2% ± 6.5. The health literacy mean score was 13.3±3.6, with minimum score 0 and maximum score 16. The mean percentage score of attitudes towards Pap smear was 64.8%±9.3. Multiple linear regression analysis demonstrated significant relationship between health literacy (p=0.047) and knowledge of Pap smear (p<0.001) with attitude towards Pap smear. Conclusion: A higher health literacy with high knowledge of Pap smear improves the attitude towards Pap smear. Pre-marital course is an opportunistic platform to disseminate information to improve health literacy and knowledge of cervical cancer and Pap smear screening.     

Impact of the earthquake during COVID-19 lockdown on fracture admission at a tertiary trauma centre in Croatia

PurposeTo determine the impact of an earthquake during COVID-19 lockdown on fracture admission at a tertiary trauma centre in Croatia.MethodsA case-control study was performed at the tertiary trauma centre registry. Two different periods were studied. The case group included a period during COVID-19 lockdown right after the earthquakes until the end of the confinement period in Croatia. And the control group corresponded to the equivalent period in 2019. We identified all consecutive patients who were admitted due to urgent care requirements for the musculoskeletal trauma. Patient''s demographic data and admitting diagnoses were assessed. Data were analyzed by statistical procedures using the program MedCalc statistical software version 16.4.3.ResultsWe identified 178 emergency admissions due to musculoskeletal trauma. During the COVID-19 lockdown and post-earthquake period, there was a drastic reduction in total admissions (359 vs. 662; p < 0.0001) with an increased proportion of trauma admissions within the emergency admissions (34.9% vs. 26.5%; p = 0.02926, Z = −2.1825). Furthermore, in the case group there was a significant increase in hospital admissions due to ankle/foot trauma (11 vs. 2, p = 0.0126) and a trend towards a decrease in the admissions due to tibia fractures (5 vs. 12, p = 0.0896), however without statistical significance. Also, an increased proportion of women within the group of femoral fractures in both case group (81.6% vs. 52.6%, p = 0.00194, Z = 3.1033) and the control group (82.3% vs. 60.5%, p = 0.0232, Z = 2.2742) was observed. In both analyzed periods, the osteoporotic hip fracture was the most common independent admitting diagnosis.ConclusionIt is crucial to understand how natural disasters like earthquakes influence the pattern of trauma admissions during a coexisting pandemic. Accordingly, healthcare systems have to be prepared for an increased influx of certain pathology, like foot and ankle trauma.     

Left Atrial Deformation Parameters Predict Left Atrial Appendage Function and Thrombus in Patients in Sinus Rhythm with Suspected Cardioembolic Stroke: A Speckle Tracking and Transesophageal Echocardiography Study

The aim of this study was to evaluate left atrial deformations using speckle tracking echocardiography for predicting left atrial appendage (LAA) thrombus in patients with suspected cardioembolic stroke who were in normal sinus rhythm. A total of 153 ischemic stroke patients (89 males, 64 females) in sinus rhythm who were suspected of having cardioembolism were included in the study. The patients underwent conventional two‐dimensional (2D) echocardiogram and 2D speckle tracking echocardiogram of the left atrium. Left atrial peak strain (LA‐4C‐RES) and left atrial precontraction strain (LA‐4C‐PUMP) were measured. Patients were divided into 2 groups according to the presence of thrombus in the LAA in transesophageal echocardiography. Both LA‐4C‐RES and LA‐4C‐PUMP values were found to be significantly lower in patients with LAA thrombus (11.8 ± 1.4% vs. 33 ± 12%, P < 0.001 and 5.8 ± 1.3% vs. 14.2 ± 5.3%, P < 0.001, respectively). A good inverse correlation was present between LA‐4C‐RES values and LAA morphologic parameters (with LAA area: r = ?0.70, P < 0.001, with LAA length: r = ?0.60, P < 0.001), and a good positive correlation was present with LAA emptying velocity with pulse Doppler (r = 0.74, P < 0.001). The area under the receiver‐operating characteristic curve of the LA‐4C‐RES was 0.94 (0.90–0.98, P < 0.001), for the LA‐4C‐PUMP, the area was 0.92 (0.87–0.96, P < 0.001) to predict LAA thrombus. Left atrial deformation parameters measured by 2D speckle tracking method was found to predict impaired LAA functions and the presence of LAA thrombus in ischemic stroke patients with suspected cardioembolism, but who are in sinus rhythm.     

Acute primary angle closure in an Asian population: long-term outcome of the fellow eye after prophylactic laser peripheral iridotomy

PURPOSE: To study the long-term outcome of fellow eyes of Asian patients with acute primary angle closure (APAC) who underwent prophylactic laser peripheral iridotomy (LPI). DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Ninety-six consecutive patients with APAC at presentation to one Singapore hospital from January 1990 through December 1994. METHODS: The presenting features of the fellow eye were recorded, and the subsequent long-term intraocular pressure (IOP) outcome after LPI was analyzed. All fellow eyes were initially treated with pilocarpine 2% eyedrops four times daily before LPI, which was performed within 1 week of presentation. For any eye, a rise in IOP during follow-up was defined as a rise in IOP requiring treatment by medication or surgery. MAIN OUTCOME MEASURES: Incidence of acute angle closure and IOP. RESULTS: The mean follow-up period was 50.8 months (range, 9-99 months). Of the 96 patients, 15 patients had bilateral APAC, and APAC developed in one fellow eye before LPI could be performed. The remaining 80 fellow eyes were studied. No cases of APAC developed after prophylactic LPI. Seventy-one fellow eyes (88.8%) were successfully treated with LPI alone without the need for additional glaucoma treatment in the long term. Seven eyes (8.8%) had IOPs of 21 mmHg or less on presentation, but a rise in IOP developed on follow-up despite the presence of a patent LPI. Two fellow eyes (2.5%) had signs of preexisting chronic angle closure glaucoma at presentation and required further glaucoma treatment even after LPI. There were no significant complications from the procedure in any of the fellow eyes studied. CONCLUSIONS: In this Asian population with APAC, prophylactic LPI is safe and effective in preventing acute angle closure in fellow eyes. In addition, prophylactic LPI prevents long-term rise in IOP in 88.8% of fellow eyes (with approximately 4 years of follow-up). However, because a small proportion of fellow eyes did experience a rise in IOP within the first year, despite the presence of a patent LPI, close monitoring is still advised in the follow-up of fellow eyes of patients with APAC.     

Chronic angle-closure with glaucomatous damage: long-term clinical course in a North American population and comparison with an Asian population

PURPOSE: To study the long-term clinical course of North American chronic angle-closure glaucoma (CACG) patients with optic disc damage and visual field loss in the presence of an angle closed at least partially by peripheral anterior synechiae and to compare it with a similar group of Singaporean patients. DESIGN: A retrospective, interventional case-control study series. PARTICIPANTS: Fifty-one patients (80 eyes) diagnosed with CACG with glaucomatous optic nerve head and visual field damage at a New York hospital from January 1990 through December 1994. All study eyes underwent laser peripheral iridotomy (LPI). METHODS: The presenting features, management, and subsequent long-term intraocular pressure (IOP) outcome were analyzed and compared with 65 Asian patients (83 eyes) from a Singapore hospital who were similarly diagnosed during the same period. MAIN OUTCOME MEASURES: The long-term outcome after LPI was assessed in terms of IOP and the requirement for additional therapy. RESULTS: The mean presenting IOP was higher in the Singapore eyes (40 +/- 15 mmHg) compared with the New York eyes (31 +/- 12.5 mmHg). All 80 New York eyes (100%) and 78 of 83 Singapore eyes (94%) required further treatment to control IOP during follow-up. Of the eyes with a subsequent rise in IOP, 33 of 80 eyes (41.3%) compared with 34 of 83 eyes (41.0%) of the Singapore patients were controlled with additional topical medication. Of the New York eyes, 25 of 80 (31.3%) eventually underwent filtering surgery, compared with 44 of 83 (53.0%) in the Singapore study. The other 22 eyes (27.5%) in the New York group went on to additional laser procedures, peripheral iridoplasty, laser trabeculoplasty, or a combination thereof, after which IOPs were controlled and no surgery was required. There was no similar comparison for the Singapore group, because these eyes went directly on to surgery. CONCLUSIONS: Despite the presence of a patent LPI, most eyes with CACG presenting with elevated IOP and having both optic disc and visual field damage in both populations required further treatment to control IOP. Results in the American population are similar to that reported in Asian patients.