Dangerous dietary supplements: Garcinia cambogia-associated hepatic failure requiring transplantation.

Commercial dietary supplements are marketed as a panacea for the morbidly obese seeking sustainable weight-loss. Unfortunately, many claims cited by supplements are unsupported and inadequately regulated. Most concerning, however, are the associated harmful side effects, often unrecognized by consumers. Garcinia cambogia extract and Garcinia cambogia containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we report the first known case of fulminant hepatic failure associated with this dietary supplement. One active ingredient in this supplement is hydroxycitric acid, an active ingredient also found in weight-loss supplements banned by the Food and Drug Administration in 2009 for hepatotoxicity. Heightened awareness of the dangers of dietary supplements such as Garcinia cambogia is imperative to prevent hepatoxicity and potential fulminant hepatic failure in additional patients

Utilizing Combined Methodologies to Define the Role of Plasma Membrane Delivery During Axon Branching and Neuronal Morphogenesis

During neural development, growing axons extend to multiple synaptic partners by elaborating axonal branches. Axon branching is promoted by extracellular guidance cues like netrin-1 and results in dramatic increases to the surface area of the axonal plasma membrane. Netrin-1-dependent axon branching likely involves temporal and spatial control of plasma membrane expansion, the components of which are supplied through exocytic vesicle fusion. These fusion events are preceded by formation of SNARE complexes, comprising a v-SNARE, such as VAMP2 (vesicle-associated membrane protein 2), and plasma membrane t-SNAREs, syntaxin-1 and SNAP25 (synaptosomal-associated protein 25). Detailed herein is a multi-pronged approach used to examine the role of SNARE mediated exocytosis in axon branching. The strength of the combined approach is data acquisition at a range of spatial and temporal resolutions, spanning from the dynamics of single vesicle fusion events in individual neurons to SNARE complex formation and axon branching in populations of cultured neurons. This protocol takes advantage of established biochemical approaches to assay levels of endogenous SNARE complexes and Total Internal Reflection Fluorescence (TIRF) microscopy of cortical neurons expressing VAMP2 tagged with a pH-sensitive GFP (VAMP2-pHlourin) to identify netrin-1 dependent changes in exocytic activity in individual neurons. To elucidate the timing of netrin-1-dependent branching, time-lapse differential interference contrast (DIC) microscopy of single neurons over the order of hours is utilized. Fixed cell immunofluorescence paired with botulinum neurotoxins that cleave SNARE machinery and block exocytosis demonstrates that netrin-1 dependent axon branching requires SNARE-mediated exocytic activity

Watermarks in the Sand: Impossibility of Strong Watermarking for Generative Models

Watermarking generative models consists of planting a statistical signal (watermark) in a model's output so that it can be later verified that the output was generated by the given model. A strong watermarking scheme satisfies the property that a computationally bounded attacker cannot erase the watermark without causing significant quality degradation. In this paper, we study the (im)possibility of strong watermarking schemes. We prove that, under well-specified and natural assumptions, strong watermarking is impossible to achieve. This holds even in the private detection algorithm setting, where the watermark insertion and detection algorithms share a secret key, unknown to the attacker. To prove this result, we introduce a generic efficient watermark attack; the attacker is not required to know the private key of the scheme or even which scheme is used. Our attack is based on two assumptions: (1) The attacker has access to a "quality oracle" that can evaluate whether a candidate output is a high-quality response to a prompt, and (2) The attacker has access to a "perturbation oracle" which can modify an output with a nontrivial probability of maintaining quality, and which induces an efficiently mixing random walk on high-quality outputs. We argue that both assumptions can be satisfied in practice by an attacker with weaker computational capabilities than the watermarked model itself, to which the attacker has only black-box access. Furthermore, our assumptions will likely only be easier to satisfy over time as models grow in capabilities and modalities. We demonstrate the feasibility of our attack by instantiating it to attack three existing watermarking schemes for large language models: Kirchenbauer et al. (2023), Kuditipudi et al. (2023), and Zhao et al. (2023). The same attack successfully removes the watermarks planted by all three schemes, with only minor quality degradation.Comment: Blog post: https://www.harvard.edu/kempner-institute/2023/11/09/watermarking-in-the-sand

Mucinous intrahepatic cholangiocarcinoma: a distinct variant

Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2 cm and 6.0 cm, respectively. The majority of patients (83%) with mucinous iCC presented at T3 stage or above, compared to 28% of the conventional group (p < 0.01). Three patients with mucinous iCC (50%) died within 1 year. The average survival time of patients with mucinous iCCs was significantly reduced compared to that of conventional group (9 months vs 2 years; P < .001). Immunohistochemistry was performed on 6 mucinous and 12 conventional iCCs with matched age, sex and stage, which revealed positive immunoreactivity in MUC1 (83% vs 58%), MUC2 (33% vs 17%), MUC5AC (100% vs 42%), MUC6 (50% vs 0), CK7 (83% vs 83%), CK20 (0 vs 17%), and CDX2 (17% vs 0) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes 7.2% of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20-/CDX2- and microsatellite stable. Patients with mucinous iCC likely present at advanced stage upon diagnosis with shorter survival time compared to the conventional counterparts

Lymphovascular Invasion in Colorectal Cancer: An Interobserver Variability Study

Background: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with Stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. Design: Fifty cases of AJCC stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty H&E slides (one from each case) were circulated to 6 GI pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (κ)statistics, which correct for agreement by chance, and for percent agreement. Results: The average κ values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Figure 1). Agreement was fair for H&E small vessel invasion (κ = 0.28; 95%CI 0.22–0.34). The least agreement was seen in interpretation of H&E large vessel invasion (κ = 0.18; 95%CI 0.11–0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, κ = 0.42, 95%CI 0.20–0.63, small vessel, κ = 0.26, 95%CI 0.10–0.42) and D2-40 (κ = 0.32, 95%CI 0.21–0.42). Conclusions: Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of lymphovascular invasion, as this assessment may impact patient prognosis and thus change the course of clinical treatment

Seed-set evaluation of four male-sterile, female-fertile soybean lines using alfalfa leafcutting bees and honey bees as pollinators

Male-sterile, female-fertile plants were used to produce hybrid soybean seed. Manual cross-pollination using male-sterile plants to produce large quantities of hybrid seed is difficult and time-consuming because of the low success rate in cross-pollination. Insect pollinators may be suitable vectors to transfer pollen, but the most suitable vector for pollen transfer from the male parent to the female parent has not been identified for soybean. The objective of the present study was to evaluate seed-set on four male-sterile, female-fertile soybean lines by using alfalfa leafcutting bees (Megachile rotundata (F.)) and honey bees (Apis mellifera (L.)) as pollinators. Seed-set was evaluated in summers 2003 and 2005 near Ames, Iowa, USA and in summers 2003, 2004, and 2005 near Wooster, Ohio, USA. Neither the effect of pollinator species nor the interaction effect of pollinator species×location was significant for any year. Honey bees performed similarly to alfalfa leafcutting bees at both locations. The results indicated significant differences for seed-set among male-sterile lines, suggesting preferential pollination. Male-sterile lines, ms1(Urbana) and ms2 (Ames 2), had higher cross-pollinated seed-set compared to ms6 (Ames 1), and ms6 (Corsoy 79). At the Ames location, ms1ms1 (Urbana) plants had the highest seed-set (50·16 seeds per male-sterile plant in 2005). At the Wooster location, ms1ms1 (Urbana) plants also had the highest seed-set (92·04 seeds per male-sterile plant) in 2005. Costs and local conditions need to be addressed to support the choice of either pollinator species as a pollination vector to produce hybrid soybean seed