A Primer on the Current State-of-the-Science Neoadjuvant and Adjuvant Therapy for Patients with Locally Advanced Rectal Adenocarcinomas

Patients with rectal cancers, due to the unique location of the tumor, have a recurrence pattern distinct from colon cancers. Advances in adjuvant therapy over the last three decades have played an important role in improving patient outcomes. This article serves to review the clinical studies that lay the basis for our current standard-of-care treatment of patients with locally advanced rectal cancer, as well as touch upon future ongoing experimental clinical trials of adjuvant chemoradiation therapy

Growth dynamics of a Bose-Einstein condensate in a dimple trap without cooling

We study the formation of a Bose-Einstein condensate in a cigar-shaped three-dimensional harmonic trap, induced by the controlled addition of an attractive "dimple" potential along the weak axis. In this manner we are able to induce condensation without cooling due to a localized increase in the phase space density. We perform a quantitative analysis of the thermodynamic transformation in both the sudden and adiabatic regimes for a range of dimple widths and depths. We find good agreement with equilibrium calculations based on self-consistent semiclassical Hartree-Fock theory describing the condensate and thermal cloud. We observe there is an optimal dimple depth that results in a maximum in the condensate fraction. We also study the non-equilibrium dynamics of condensate formation in the sudden turn-on regime, finding good agreement for the observed time dependence of the condensate fraction with calculations based on quantum kinetic theory.Comment: v1: 9 pages, 7 figures, submitted to Phys. Rev. A; v2: 10 pages, 8 figures, fixed typos, added references, additional details on experimental procedure, values of phase-space density, new figure and discussion on effects of three-body loss in Appendix B (replaced with published version

Diagnostic accuracy of a point-of-care urine tenofovir assay, and associations with HIV viraemia and drug resistance among people receiving dolutegravir and efavirenz-based antiretroviral therapy

Introduction: Novel point-of-care assays which measure urine tenofovir (TFV) concentrations may have a role in improving adherence monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). However, further studies of their diagnostic accuracy, and whether results are associated with viraemia and drug resistance, are needed to guide their use, particularly in the context of the global dolutegravir rollout. Methods: We conducted a cross-sectional evaluation among PLHIV receiving first-line ART containing tenofovir disoproxil fumarate at enrolment into a randomized trial in two South African public sector clinics. We calculated the diagnostic accuracy of the Abbott point-of-care immunoassay to detect urine TFV compared to liquid chromatography-tandem mass spectrometry (LC-MS/MS). We evaluated the association between point-of-care urine TFV results and self-reported adherence, viraemia ≥1000 copies/ml and HIV drug resistance, among people receiving either efavirenz or dolutegravir-based ART. Results: Between August 2020 and March 2022, we enrolled 124 participants. The median age was 39 (IQR 34–45) years, 55% were women, 74 (59.7%) were receiving efavirenz and 50 (40.3%) dolutegravir. The sensitivity and specificity of the immunoassay to detect urine TFV ≥1500 ng/ml compared to LC-MS/MS were 96.1% (95% CI 90.0−98.8) and 95.2% (75.3−100.0), respectively. Urine TFV results were associated with short (p<0.001) and medium-term (p = 0.036) self-reported adherence. Overall, 44/124 (35.5%) had viraemia, which was associated with undetectable TFV in those receiving efavirenz (OR 6.01, 1.27−39.0, p = 0.014) and dolutegravir (OR 25.7, 4.20−294.8, p<0.001). However, in those with viraemia while receiving efavirenz, 8/27 (29.6%) had undetectable urine TFV, compared to 11/17 (64.7%) of those receiving dolutegravir. Drug resistance was detected in 23/27 (85.2%) of those receiving efavirenz and only 1/16 (6.3%) of those receiving dolutegravir. There was no association between urine TFV results and drug resistance. Conclusions: Among PLHIV receiving ART, a rapid urine TFV immunoassay can be used to accurately monitor urine TFV levels compared to the gold standard of LC-MS/MS. Undetectable point-of-care urine TFV results were associated with viraemia, particularly among people receiving dolutegravir. Trial registration: Pan-African Clinical Trials Registry: PACTR202001785886049

Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir based antiretroviral therapy

Objective: We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia. Design: Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART). Methods: We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia ≥1000 copies/mL using logistic regression models. In exploratory analyses, we used receiver operating curves to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia. Results: Among 124 participants, 68 (54.8%) were women, median age was 39 years (interquartile range [IQR] 34–45) and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV (1000 ng/mL increase, odds ratio [OR] 0.97 95%CI 0.94–0.99, p = 0.005) and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95%CI 0.67–0.86, p < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV p = 0.072, DBS TFV-DP p = 0.003). Nagelkerke Pseudo-R2 for the DBS TFV-DP models was higher than for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml. Conclusions: Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir

Mutation of the Conserved Calcium-Binding Motif in Neisseria gonorrhoeae PilC1 Impacts Adhesion but Not Piliation

ABSTRACT Neisseria gonorrhoeae PilC1 is a member of the PilC family of type IV pilus-associated adhesins found in Neisseria species and other type IV pilus-producing genera. Previously, a calcium-binding domain was described in the C-terminal domains of PilY1 of Pseudomonas aeruginosa and in PilC1 and PilC2 of Kingella kingae . Genetic analysis of N. gonorrhoeae revealed a similar calcium-binding motif in PilC1. To evaluate the potential significance of this calcium-binding region in N. gonorrhoeae , we produced recombinant full-length PilC1 and a PilC1 C-terminal domain fragment. We show that, while alterations of the calcium-binding motif disrupted the ability of PilC1 to bind calcium, they did not grossly affect the secondary structure of the protein. Furthermore, we demonstrate that both full-length wild-type PilC1 and full-length calcium-binding-deficient PilC1 inhibited gonococcal adherence to cultured human cervical epithelial cells, unlike the truncated PilC1 C-terminal domain. Similar to PilC1 in K. kingae , but in contrast to the calcium-binding mutant of P. aeruginosa PilY1, an equivalent mutation in N. gonorrhoeae PilC1 produced normal amounts of pili. However, the N. gonorrhoeae PilC1 calcium-binding mutant still had partial defects in gonococcal adhesion to ME180 cells and genetic transformation, which are both essential virulence factors in this human pathogen. Thus, we conclude that calcium binding to PilC1 plays a critical role in pilus function in N. gonorrhoeae

First Results from COPSS: The CO Power Spectrum Survey

We present constraints on the abundance of carbon monoxide in the early universe from the CO Power Spectrum Survey. We utilize a data set collected between 2005 and 2008 using the Sunyaev–Zel'dovich Array (SZA), which was previously used to measure arcminute-scale fluctuations of the cosmic microwave background. This data set features observations of 44 fields, covering an effective area of 1.7 square degrees, over a frequency range of 27–35 GHz. Using the technique of intensity mapping, we are able to probe the CO(1–0) transition, with sensitivity to spatial modes between k = 0.5–2 h Mpc^(−1) over a range in redshift of z = 2.3–3.3, spanning a comoving volume of 3.6 × 10^6 h^(−3) Mpc^3. We demonstrate our ability to mitigate foregrounds, and present estimates of the impact of continuum sources on our measurement. We constrain the CO power spectrum to P_(CO) < 2.6 × 10^4 μK^2 (h^(−1) Mpc)^3, or Δ^2_(CO)(k = 1 h Mpc^(−1)) < 1.3 × 10^3 μK^2, at 95% confidence. This limit resides near optimistic predictions for the CO power spectrum. Under the assumption that CO emission is proportional to halo mass during bursts of active star formation, this corresponds to a limit on the ratio of CO(1–0) luminosity to host halo mass of A_(CO) < 1.2 × 10^(−5) L⊙_ M_⊙^(−1). Further assuming a Milky Way-like conversion factor between CO luminosity and molecular gas mass (α_(CO) = 4.3 M_⊙ (K km s^(−1) pc^(−2))^(−1)), we constrain the global density of molecular gas to ρ_(z~3) (M_H_2) ⩽ 2.8 x 10^8 M_☉ Mpc^(-3)

Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both “amoeboid-like” and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis

The longer-term effects of access to HIV self-tests on HIV testing frequency in high-risk gay and bisexual men: follow-up data from a randomised controlled trial

Background: A wait-list randomised controlled trial in Australia (FORTH) in high-risk gay and bisexual men (GBM) showed access to free HIV self-tests (HIVSTs) doubled the frequency of HIV testing in year 1 to reach guideline recommended levels of 4 tests per year, compared to two tests per year in the standard-care arm (facility-based testing). In year 2, men in both arms had access to HIVSTs. We assessed if the effect was maintained for a further 12 months. Methods: Participants included GBM reporting condomless anal intercourse or > 5 male partners in the past 3 months. We included men who had completed at least one survey in both year 1 and 2 and calculated the mean tests per person, based on the validated self-report and clinic records. We used Poisson regression and random effects Poisson regression models to compare the overall testing frequency by study arm, year and testing modality (HIVST/facility-based test). Findings: Overall, 362 men completed at least one survey in year 1 and 343 in year 2. Among men in the intervention arm (access to HIVSTs in both years), the mean number of HIV tests in year 2 (3⋅7 overall, 2⋅3 facility-based tests, 1⋅4 HIVSTs) was lower compared to year 1 (4⋅1 overall, 1⋅7 facility-based tests, 2⋅4 HIVSTs) (RR:0⋅84, 95% CI:0⋅75-0⋅95, p=0⋅002), but higher than the standard-care arm in year 1 (2⋅0 overall, RR:1⋅71, 95% CI:1⋅48-1.97, p<0⋅001). Findings were not different when stratified by sociodemographic characteristics or recent high risk sexual history. Interpretation: In year 2, fewer HIVSTs were used on average compared to year 1, but access to free HIVSTs enabled more men to maintain higher HIV testing frequency, compared with facility-based testing only. HIV self-testing should be a key component of HIV testing and prevention strategies. Funding:: This work was supported by grant 568971 from the National Health and Medical Research Council of Australia